基质金属蛋白酶1，3，9基因单核苷酸多态性与收缩期高血压发病机制的研究
摘要
【研究背景】
收缩期高血压(ISH)是以收缩压增高和脉压差增大为特点的一种特殊类型高血压,常见于老年人,具有较高的致死、致残率,已成为人们研究的热点。随着我国人口老年化进程的加剧和人群疾病谱的变化,ISH患病率逐年增加。ISH作为原发性高血压的一种特殊亚型,发病机制复杂且远未阐明,目前认为是遗传因素和环境因素共同作用的结果。随着分子遗传学的发展,遗传因素在原发性高血压发病机制中的地位越来越受到重视,迄今为止被研究过的高血压候选基因至少有150种,它们涉及肾素-血管紧张素-醛固酮系统、交感神经系统、下丘脑-垂体轴、内皮素、利钠肽、激肽释放酶-激肽系统、类固醇激素、前列腺素、生长因子、激素、骨架蛋白、粘附分子、细胞内信使、脂质代谢、糖代谢、载脂蛋白、离子通道和转运体等,但各家报道结果不一致,还没有一个基因或基因变异被肯定与原发性高血压相关。原发性高血压等复杂性状疾病有以下共同特点：遗传模式未确定、遗传异质性强、外显率低、多个基因参与、单一基因的作用微弱等。虽然血压升高是高血压患者的共同表型,但患者的发病机制和与之相关的基因变异千差万别。因此对遗传异质性很强的高血压群体进行基因多态性分析,尤其当样本量不够大时,研究结果不一致就不足为奇了。我们认为在目前诊断的原发性高血压患者中可能包括了太多的亚型,笼而统之的研究难以获得结果。选择一些特殊的亚型进行研究可能成为阐明高血压发病机制的突破口。
动脉僵硬度增加、顺应性降低被认为是ISH典型的病理生理学特点,通过构建ISH模型人们发现促进动脉硬化的因素都可能导致ISH的发生发展。近来研究表明,弹性蛋白在大动脉中层中的含量和结构的改变都能导致动脉弹性降低,僵硬度增加。且国外众多研究还表明,弹性蛋白基因多态性及单体型与动脉僵硬度密切相关。Hanon等研究表明弹性蛋白SNP位点(rs2071307, exon16)与老年患者的弹性动脉的舒张性密切相关。Hiroyuki等认为弹性蛋白SNP位点(rs34208922,3'-UTR(+502)A)的基因变异可使弹性蛋白mRNA的表达下调,从而导致动脉壁弹性蛋白含量降低及功能的改变。Iwai等进一步证实该位点的变异与动脉僵硬度及收缩压升高密切相关。还有研究表明弹性蛋白基因多态性(rs41350445 and SNP rs41500150 in exon 5, rs34945509 in exon 20)可能在家族性颅内动脉瘤和蛛网膜下腔出血的发生、发展过程中起重要作用,其作用机制为以上SNP位点基因变异导致颅内动脉僵硬度增加,动脉顺应性降低所致。通过对弹性蛋白基因的这几个SNP位点的研究,我们也发现了rs2071307 (exon16)、rs34208922 (3'-UTR(+502)A)这两个SNP位点与ISH密切相关。
近年来,随着高血压病发病机制的深入研究,大动脉重构和功能的改变逐渐成为研究的热点。高血压病大动脉功能改变与重构是心血管病的独立预后危险因素。血管重构是指人血管容积、组成成分、构型和弹性等的改变。细胞外基质(ECM)的重组启动血管构型的变化,因此降解ECM最主要的酶--基质金属蛋白酶(MMPs)成为研究生理、病理性血管重构的焦点。ECM是由大分子构成的错综复杂的网络。构成ECM的大分子种类繁多,可归纳为四大类：胶原、糖蛋白、蛋白聚糖与透明质酸、弹性蛋白。基质金属蛋白酶(MMPs)是一组含能够降解ECM的蛋白酶,根据结构和底物特异性不同可分为5大类：间质胶原酶(MMP-1、MMP-8、MMP-13、MMP-18)、Ⅳ型胶原酶、明胶酶(MMP-2、MMP-9)、基质溶解素(MMP-3、MMP-7、MMP-10)、膜型(MMP-14、MMP-15、MMP-16)。MMPs活性增加及蛋白表达上调都可能导致血管内结构蛋白含量的改变及血管重构,同时MMPs的活性也能被组织抑制因子(TIMP)所抑制。由于MMPs具有导致血管重构的作用,MMPs被认定在某些心血管疾病(粥样斑块形成及破裂、心肌梗死及中风等)的发生发展及转归的过程中发挥重要作用。近年研究认为MMPs也与动脉硬化及血压升高密切相关。MMP-3是MMP家族中的一种关键酶,能影响其它基质金属酶的活性和作用,在保持大血管内基质稳态发挥着重要作用。其单核苷酸多态性的研究表明,SNP(rs3025058,5A/6A)与冠状动脉粥样硬化程度以及心肌梗死的危险性密切相关；体内及体外试验表明,血管组织内MMP-3 mRNA水平及蛋白水平在5A纯合子中表达最高,而在6A纯合子中表达最低,5A/6A杂合子居中。此外,5A纯合子的人群与5A/6A及6A纯合子相比具有动脉僵硬度显著增加和血压明显升高的特征。MMP-9是人们研究最多的一种基质金属蛋白酶,研究表明其活性及单核苷酸多态性不仅在冠心病的发生、发展中发挥重要作用,也与动脉硬化密切相关。Yamin等通过对MMP-2、MMP-9活性与ISH和动脉僵硬度的关系研究发现,MMP-9活性与ISH和动脉僵硬度密切相关,并推测MMP-9可能在ISH的发生发展过程中起主要作用。Lehoux等通过将大鼠颈动脉在压力不同的培养基中(10mmHg、80mmHg、150mmHg)放置3天后,测定MMP-2、MMP-9的活性,结果发现MMP-9在压力于150mmHg下较其它压力表达增强,且分别研究MMP-9缺陷及加入MMP-9活性的小鼠与血管僵硬度的关系,发现高压下血管僵硬度不再增加,认为高管腔内压力诱导的MMPs直接参与颈动脉僵硬度的增加过程,MMP-9在高血压病早期血管重构中起重要作用。最近有学者研究发现MMP-9的不同基因型对大动脉僵硬度作用不同。Medley等研究结果发现显示SNP (rs3918242, C-1562T)T纯合子及杂合子较C/C纯合子更能诱导proMMP-9的合成,增强MMP-9的活性,从而通过血管重构增加大动脉僵硬度,同时还发现T纯合子及杂合子人群与C/C纯合子人群相比动脉僵硬度显著增加,桡动脉及颈动脉收缩压、脉压显著升高。近来,Armstrong C等研究认为MMP-9 R279Q(rs17576)与颈动脉中层厚度(IMT)密切相关,MMP-1 A-519G(rs494379)、TIMP-3 T-1296C(rs5749511)在动脉硬化及血压升高方面具有重要作用,因此我们有理由认为MMP-1, MMP-3, MMP-9及TIMP-3可能为ISH的候选基因,在ISH的发生发展过程中起重要作用。
脉搏波传导速度(PWV)是评价动脉硬化的重要指标,研究表明收缩期高血压患者与双期高血压和健康人群相比PWV显著增高。晚期糖基化终产物(AGEs)近年来在评价动脉硬化方面的作用得到了进一步的肯定,研究认为AGEs与血管内结构蛋白通过桥接形成在动脉硬化的进程中发挥作用。血流介导的血管舒张功能(FMD)是评价内皮依赖性血管舒张功能的主要方式,研究表明,高血压患者普遍存在FMD受损的特点,并发现PWV越高FMD越低,FMD与PWV呈显著负相关。一氧化氮(NO)与内皮素-1(ET-1)分别为内皮衍生性的主要血管舒张和收缩因子,起到调节血管舒张和收缩的功能,在动脉硬化的发生发展过程中起主要作用。
我们假设MMP-1 rs494379 (A-519G), MMP-3 rs3025058 (5A/6A), MMP-9 rs17576 (R279Q), MMP-9 rs3918242 (C-1562T), TIMP-3 rs5749511 (T-1296C)5个SNP位点与收缩期高血压密切相关,并通过影响PWV、AGEs、FMD、NO、ET-1而发挥作用。
本课题旨在研究以上5个SNP位点与收缩期高血压的关系,并探讨它们与PWV、AGEs、FMD、NO、ET-1等的关系,从而揭示基质金属蛋白酶SNP的可能作用机制,为阐明收缩期高血压的发生发展提供科学依据。
第一章基质金属蛋白酶1,3,9及组织抑制因子3基因单核苷酸多态性与收缩期高血压关系的研究
目的研究基质金属蛋白酶1,3,9及组织抑制因子3基因单核苷酸多态性与收缩期高血压的关系。
方法从2005年1月至2008年12月选取广州、湛江、乌鲁木齐等三地503例收缩期高血压患者(ISH组),481例原发性高血压患者(EH组,非收缩期高血压)以及年龄相匹配的244例健康人群(NT组),采用连接酶检测反应(LDR-PCR)测定各患者基质金属蛋白酶1,3,9及组织抑制因子3基因5个SNP位点MMP-1rs494379 (A-519G), MMP-3 rs3025058 (5A/6A), MMP-9 rs17576 (R279Q), MMP-9 rs3918242(C-1562T), TIMP-3 rs5749511 (T-1296C)的基因表型,分析各SNP位点中的等位基因与收缩期高血压之间的关系,并进行单体型分析。
结果多元logistic回归分析结果显示,在控制年龄、甘油三酯、低密度脂蛋白等混杂因素的情况下,MMP-3基因SNP位点rs3025058(5A/6A)中5A等位基因和MMP-9基因SNP位点rs3918242(C-1562T)中的T等位基因与收缩期高血压密切相关(P<0.001,Pcorr＜0.003；P=-0.009,Pcorr=0.027)；其他各SNP位点中的等位基因与收缩期高血压无显著相关性；通过单体型分析还发现单体5A/G/C与原发性高血压相关,单体6A/A/T与收缩期高血压密切相关(Permutation p=0.0258; Permutation p=0.000002)。
结论MMP-3和MMP-9基因的变异可显著增加我国汉族人群发生收缩期高血压的危险性。
第二章基质金属蛋白酶3,9基因单核苷酸多态性与动脉硬化和血管内皮功能的关系
目的探讨基质金属蛋白酶3,9基因单核苷酸多态性与脉搏波传导速度(PWV)、晚期糖基化终产物(AGEs)和血流介导的血管舒张功能(FMD)、内皮素-1(ET-1)、一氧化氮(NO)的关系。
方法从2007年7月至2008年12月选取广州、湛江、乌鲁木齐等三地169例收缩期高血压患者(ISH组),134例原发性高血压患者(EH组,非收缩期高血压)以及年龄相匹配的71例健康人群(NT组),采用动脉硬化装置检测肱-踝脉搏波传导速度(baPWV),采用超声技术测定FMD,采用ELISA法检测患者外周血清中的AGEs、ET-1,并采用Griess反应法测定外周血中的NO浓度。分析各组人群中基质金属蛋白酶3,9基因rs3025058(5A/6A)、rs3918242(C-1562T)SNP位点中的不同基因表型个体间baPWV、FMD、AGEs、ET-1及NO之间的差异。
结果MMP-3基因SNP位点rs3025058(5A/6A)中5A/5A突变型纯合子患者的PWV显著高于5A/6A杂合子及6A/6A野生型纯合子患者(P<0.01),而MMP-3基因SNP位点rs3025058(5A/6A)中5A/5A突变型纯合子患者的FMD显著低于5A/6A杂合子及6A/6A野生型纯合子患者(P<0.01)；MMP-9基因SNP位点rs3918242(C-1562T)中T/T突变型纯合子患者的PWV显著高于C/T杂合子及T/T野生型纯合子患者(P<0.01),而MMP-9基因SNP位点rs3918242(C-1562T)中T/T突变型纯合子患者的FMD显著低于C/T杂合子及T/T野生型纯合子患者(P<0.01)。
结论MMP-3及MMP-9基因单核苷酸多态性与大动脉硬化和血管内皮功能障碍密切相关。
第三章收缩期高血压患者血清中晚期糖基化终产物与血管内皮功能的关系
目的探讨收缩期高血压患者血清中晚期糖基化终产物(AGEs)与血流介导的血管舒张功能(FMD)间的关系及其致内皮功能异常的作用。
方法选择收缩期高血压患者120例作为ISH组,原发性高血压患者(非收缩期高血压)120例作为DH组,年龄与之相匹配的健康人群70例作为NT组,采用SUN-8800动脉硬化检测仪测定PWV,超声技术测定FMD, ELISA检测受试者外周血清中AGEs和ET-1, Griess法测定外周血中NO含量。
结果收缩期高血压组的PWV、AGEs、ET-1显著高于原发性高血压组及健康对照组(P<0.05)；收缩期高血压组及原发性高血压组FMD、NO显著低于健康对照组(P<0.05),而FMD、NO在收缩期高血压组及原发性高血压组间无显著性差异；AGEs与cfPWV、ET-1呈显著正相关(r=0.525,P=0.000；r=0.863,P=0.000)；AGEs与FMD、NO呈显著负相关(r=-0.635,P=0.000；r=-0.669,P=0.000)；在控制年龄、收缩压、舒张压、血糖、总胆固醇、甘油三酯、低密度脂蛋白、高密度脂蛋白的情况下AGEs与cfPWV、FMD、NO及ET-1分别呈独立相关(Rsquare=0.513,P=0.000；R square=0.455,P=0.000；R square=0.453,P=0.000；R square=0.769,P=0.000)
结论AGEs是导致血管内皮功能异常的独立危险因素,可能在收缩期高血压的发生发展过程中起一定作用。
第四章单纯收缩期高血压患者血管内皮功能与左室肥厚的关系
目的探讨单纯收缩期高血压(ISH)患者血流依赖性血管舒张功能(FMD)与左心室肥厚的关系。
方法选择200例ISH患者,根据左心室重量指数分为左心室肥厚组(LVH,73例),非左心室肥厚组(NLVH,127例),同期选择年龄匹配的健康人群50例作为对照组,采用超声技术测定FMD,ELISA法检测受试者外周血清中晚期糖基化终产物(AGEs)和内皮素-1(ET-1),Griess法测定外周血中一氧化氮(NO)含量。
结果与NLVH组及对照组相比,LVH组FMD.NO均显著降低,而AGEs及ET-1均显著升高；左心室重量指数与AGEs.ET-1呈显著正相关(r=0.639,P=0.015；r=0.428,P=0.036),而与FMD及NO呈显著负相关(r=-0.718,P=0.003；r=-0.337,P=0.041)；FMD及AGEs与左心室肥厚呈独立相关(P=0.027,P=0.035)；随着FMD降低、AGEs的增加左室肥厚发病的危险性均显著增加。
结论血管内皮功能减退和大动脉硬化是ISH患者左心室肥厚的独立危险因素。
第五章弹性蛋白及基质金属蛋白酶基因单核苷酸多态性在维吾尔族和汉族收缩期高血压患者间的遗传差异研究
目的探讨弹性蛋白及基质金属蛋白酶基因单核苷酸多态性在不同种族收缩期高血压患者间的遗传差异。
方法选择358例汉族收缩期高血压患者作为HISH组,200例维吾尔族收缩期高血压患者作为VISH组,采用高温连接酶检测反应(LDR-PCR)进行基因表型检测,对比分析各SNP位点中的等位基因在不同种族人群众的分布频率差异。
结果弹性蛋白基因SNP位点rs2071307中的A等位基因,rs34208922中的A等位基因以及基质金属蛋白酶-9基因SNP位点rs3918242中的T等位基因在维吾尔族收缩期高血压患者的分布频率显著高于汉族收缩期高血压患者(P=0.000)；而基质金属蛋白酶-3基因SNP位点rs3025058中的5A等位基因在两组间的分布频率无显著性差异(P=0.112)。弹性蛋白基因SNP位点rs2071307和rs34208922中的A等位基因随着收缩压的升高,等位基因频率显著增加(P=0.0079,P=0.0040),而基质金属蛋白酶-3基因SNP位点rs3025058中的5A等位基因及基质金属蛋白酶-9 SNP位点rs3918242中的T等位基因在各段收缩压中的分布频率无显著性差异(P=0.5418,P=0.5046)。
结论弹性蛋白基因SNP位点rs2071307,rs34208922可能是汉族、维吾尔族收缩期高血压的易感基因。
Backgroud
Isolated systolic hypertension of the eldly was a subtype of essential hypertension and characteristiced by elevated systolic and pulse pressure, high mortality and high morbility. Even through, ISH has been an outcome of co-contribution of environment and inherit factors, unfortunately, the pathogenesis of ISH has not been fully understood. With the development of molecular genetics, the effect of inherit factor on the Essential Hypertension morbility has been emphasized. As yet,150 candidate genes for EH had been studied, which involved in renin-angiotensin-aldosterone system(RAAS), sympathetic nervous system(SNS), low-cerebral, ganglion-master, gland-axon, endothelin(ET), natriuretic peptide, KAL-kinin system, steroid hormone(STH), prostaglandin(PG), growth factor(GF), hormone, skeleton protein, adhesion molecule, intracellular messenger, lipide metabolism, glycometabolism, apolipoprotein(APO), ion channel, and so on. But no gene variant has been confirmed to be associated with EH. Owing to characteristic of the indefinite heredity model, high genetic heterogeneity, low penetrance, more genes participated, single gene effect feeble for the EH as some polygene diseases, and relatively low samples for the studies, it was all in the day's work that the studies arrived at different results. Because of the EH including some subtypes, it is difficult to get confirmedly information about the gene association with EH, and may be as a breakthrough to interpret EH pathogenesis to chose a certain subtype.
ISH was characterized by high artery stiffness and low artery compliance, it is reported that all the factors involved in promoting artery stiffness which might be lead to ISH. It had been confirmed that the change of structure and function of elastin located in the large artery media could caused artery stiffness, and some reports about the contributions of elastin to angio-development and cardiovascular diseases revoked our interest in studying elastin gene. a deletion involving 7q11.23 that results in hemizygosity of the elastin gene has been identified as the mechanism responsible for the Williams and Buren syndrome, which is characterized by supravalvular aortic stenosis, hypertension or peripheral stenoses. Li et al had reported that elastin is an essential determinant of arterial morphogenesis, the characterization of mice haploinsufficient for elastin (Eln+/-) revealed a role for elastin in the formation of vessel wall structure. The arteries of Eln+/-mice exhibited thinner elastic lamellae and an increased number of smooth muscle cell layers. Most interestingly, these identical changes have been observed in the arteries of patients with SVAS. D'Armiento J demonstrated that mice haploinsufficient for elastin develop structural changes in vessel walls similar to those seen in patients with mutations in the elastin gene. Due to mechanical changes in the vessel wall, these animals exhibit increased mean arterial pressures. The results evoke the possibility that alterations in elastin may contribute to the development of essential hypertension in patients.
Some studies had also reported that elastin gene polymorphisms were associated with artery stiffness, Hanon O et al identified the relationship between the Ser422Gly polymorphism of the elastin gene in exon 16(rs2071307) and the distensibility of elastic arteries 9. Interestingly, Iwai N et al revealed the association of the rs34208922 polymorphism with hypertension and pulse wave velocity. Furthermore, Akagawa H et al reported that SNP(rs34208922) is involved in the reduction of elastin mRNA transcripts in vitro and ex vivo. Recently, elastin has also been suggested to be a potential candidate gene for familial intracranial aneurysms (IAs) and subarachnoid hemorrhages (SAH), which we also found defects in the internal elastic lamina. As a result, ELN may be considered as a functional candidate gene for ISH. Our study has confirmed that SNP rs34208922 and SNP rs2071307 are associated with the ISH by affecting the artery stiffness.
Isolated systolic hypertension (ISH) is characterized by increased large artery stiffness and endothelial dysfunction. The factors that cause arterial stiffening and endothelial dysfunction are likely to be involved in the development of ISH. Large artery stiffness is influenced by the relative amounts of structural proteins (particularly elastin and collagens) and by smooth muscle tone. The matrix metalloproteinases (MMPs) are a family of zinc-dependent enzymes with proteolytic activity against connective tissue proteins such as collagens, proteoglycans and elastin. Increased expression and activity of MMPs has been identified in the change of relative amounts of structural proteins and vascular remodeling. Also, the activity of MMPs is influenced by tissue inhibitors of MMP (TIMP). In addition, there is a "functional" regulation of conduit artery stiffness by smooth muscle tone, which is influenced by circulating and endothelium-derived vasoactive mediators, including nitric oxide (NO) and endothelin-1(ET-1).
Due to their major influence in vascular remodeling, MMPs have been confirmed to play an important role in the pathogenesis and prognosis of cardiovascular (CV) diseases, including atherosclerotic plaque progression, myocardial infarction and strokes. Furthermore, studies have demonstrated that MMPs gene polymorphisms are associated with artery stiffness and high blood pressure. MMP-3 plays a pivotal role in large artery matrix homeostasis; Moreover, MMP-3 can activate several other matrix metalloproteinases. This versatile enzyme is believed to play important roles in vascular and cardiac matrix remodeling. Clinical investigations have shown that MMP-3 gene polymorphisms (5A/6A) are associated with coronary atherosclerosis and risk of myocardial infarction. Additionally, MMP-3 mRNA and protein level studies from ex vivo tissue, including vascular tissue from individuals of different genotypes for the 5A/6A polymorphism(rs3025058), showed that MMP-3 expression levels are highest in 5A homozygotes, intermediate in heterozygotes and lowest in 6A homozygotes. Furthermore, individuals with 5A allele homozygotes have increased large artery stiffness and higher blood pressure compared with 5A/6A heterozygotes and 6A homozygotes. In agreement, plasma concentrations and different genotypes for the-1562 C>T polymorphism(rs3918242) of MMP-9 are not only associated with the pathogenesis of coronary disease and prognosis of patients with cardiovascular disease, but also these T-1562 allele carriers have significantly greater aortic stiffness and higher brachial systolic and pulse pressure, in addition to carotid systolic and pulse pressure. Yasmin et al demonstrated that MMP-9 levels are related to aortic stiffness, not only in ISH patients, but also in younger and healthier individuals. Furthermore, studies have revealed the MMP-9 polymorphism (-1562 C/T) seems to play a key role in the early stages of hypertensive vascular remodeling and the process of large artery stiffening. Armstrong et al revealed that MMP-9 R279Q(rs17576) is associated with internal carotid artery bulb IMT, while MMP-1 A-519G(rs494379), TIMP-3 T-1296C (rs5749511) are significantly associated with hypertension and artery stiffness. As a result, MMP-1, MMP-3, MMP-9 and TIMP-3 genes may be considered as functional candidate genes for ISH.
Pulse wave velocity (PWV) is a known marker of arterial stiffness and defined as the speed in which the pulse wave travels along the length of an artery. Recently, a role for advanced glycation end products (AGEs) in the development of arterial stiffening has been suggested, in that the resultant cross-bridge formation between AGEs and structural proteins leads to increased arterial stiffness in the model of hypertension. Endothelial function, defined as flow mediated dilatation (FMD), is estimated as the percentage increase in vessel diameter from baseline conditions to maximum vessel diameter during hyperaemia and used as a measure of endothelium-dependent vasodilatation. Clinical investigation has demonstrated the presence of impaired endothelium-dependent vasodilation in patients with hypertension as flow-mediated dilatation is inversely correlated with PWV. Nitric oxide (NO) and endothelin-1 (ET-1), the major endothelium-derived relaxing and contracting factors that regulate endothelium-dependent vasodilation, are involved in the pathogenesis of artery stiffness and hypertension.
We hypothesized that MMP-1, MMP-3, MMP-9 and TIMP-3 genes polymorphism would be involved in the development of ISH by affecting PWV, FMD, plasma AGEs, ET-1 or NO. The aim of this study was to test these hypotheses in a group of subjects with ISH, EH subjects(no ISH) and age-matched normotensive control(NT).
Part one Associations of MMP1,3,9 and TIMP3 Genes Polymorphism with Isolated Systolic Hypertension in Chinese Han Population
Objective To investigate the relationship of MMP1,3,9 and TIMP3 genes polymorphism with isolated systolic hypertension in Chinese Han population.
Methods and results We identified the genotype of the genes in 503 patients with isolated systolic hypertension,481 essential hypertension patients with elevated diastolic blood pressure and 244 age-matched normotensive controls for 5 SNPs among the participants. Multinomial logistic analyses showed that the 5A allele of rs3025058(5A/6A) in MMP3 and the T allele of rs3918242(C-1562T) in MMP9 were significantly associated with isolated systolic hypertension after adjusted by age, triglyceride, low-density lipoprotein (P< 0.001,Pcorr< 0.003;P=0.009, Pcorr=0.027). The 5A/G/C was associated with essential hypertension and 6A/A/T haplotypes were significantly associated with isolated systolic hypertension (Permutation P=0.0258; Permutation P=0.000002). Conclusion MMP3 and MMP9 genes variant seem to contribute to the development of isolated systolic hypertension
Part two Association of Polymorphisms of matrix metalloproteinasesl,3,9 Gene with artery stiffness and endothelial function in Chinese Han Patients with Isolated Systolic Hypertension
Objective To investigate the relationship of polymorphisms of matrix metalloproteinasesl,3,9 gene with pulse wave velocity(PWV), advanced glycation end products(AGEs), flow mediated dilatation(FMD), endothelin-1(ET-1) and nitric oxide(NO) in Chinese Han patients with isolated systolic hypertension.
Methods We identified the genotype of the genes in 169 patients with isolated systolic hypertension,134 essential hypertension patients with elevated diastolic blood pressure and 71 age-matched normotensive controls whom recruited from July 2007 to December 2008 for 2 SNPs and detected the brachial-ankle pulse wave velocity, advanced glycation end products, flow-mediated dilatation, endothelin-1 and nitric oxide among the participants.
Results The baPWV, AGEs and ET-1 in ISH patients were significantly higher compared with EH patients and NT controls(P<0.01, Pcorr<0.05), the FMD and NO in ISH patients and EH patients were markedly lower than NT controls(P<0.01, Pcorr<0.05), although FMD and NO in ISH patients were not significantly different with EH patients. The baPWV of different genotypes for the 5 A/6 A and C-1562T polymorphisms were significantly highest in 5A or T homozygotes, intermediate in heterozygotes and lowest in 6A or C homozygotes(P<0.01, Pcorr<0.05).By contrast, the FMD and NO were markedly lowest in 5A·or T homozygotes, intermediate in heterozygotes and highest in 6A or C homozygotes (P<0.01, Pcorr<0.05), however, there were no difference for AGEs and ET-1 in different genotype of 5A/6A and C-1562T polymorphisms.
Conclusion MMP3 and MMP9 genes variant seem to contribute to the development of isolated systolic hypertension by affecting arterial stiffness and endothelial function.
Part three The Correlation of AGEs and Vascular Function in Patients with Isolated Systolic Hypertension
Objective To investigate the correlation of advanced glycation end products(AGEs) with flow-mediated diavasoculation(FMD) and the effects of AGEs on endothelium dysfunction in patients with isolated systolic hypertension.
Methods Overall,310 subjects were enrolled in this study,120 patients with isolated systolic hypertension(ISH),120 patients with essential hypertension (DH) and 70 age-matched NT(normotension control) subjects. All of them were detected pulse wave velocity(PWV) and FMD, and the serum concentration of AGEs, ET-1 were measured by ELISA, and NO by Griess'method.
Results The PWV, AGEs and ET-1 were significantly higher in ISH patients compared with NT controls and DH patients, however, the FMD and NO in ISH patients and DH patients were markedly lower than those in NT controls. AGEs was significantly positively correlated with PWV and ET-1(r=0.525,P=0.000; r=0.863,P=0.000),but negatively correlated with FMD and NO(r=-0.635,P=0.000; r=-0.669,P=0.000);furthermore, multiple linear regression analysis showed AGEs, cfPWV were risk factors predisposed for FMD.
Conclusion AGEs was the independent risk factor of endothelium dysfunction, and may be involved in the development of ISH.
Part four Association of Endothelium-dependent Vasodilation and Left Ventricular Hypertrophy in patients with isolated systolic hypertension
Objective To investigate the correlation of endothelium-dependent vasodilation and left ventricular hypertrophy in patients with isolated systolic hypertension.
Methods Overall,250 subjects were enrolled in this study,73 isolated systolic hypertension patients (ISH) with left ventricular hypertrophy,127 ISH patients without left ventricular hypertrophy and 50 age-matched NT(normotension control) subjects according to LVMI. All of them were detected FMD by echocardiography, and the serum concentration of AGEs, ET-1 were measured by ELISA, and NO by Griess reaction.
Results The FMD and NO in ISH patients with left ventricular hypertrophy were significantly decreased(P<0.01), however, the AGEs and ET-1 were markedly increased(P<0.01); Correlation analysis showed that LVMI were negatively correlated with FMD and NO (r=-0.718,P=0.003;r=-0.337,P=0.041), and positively correlated with AGEs and ET-1(r=0.639,.P=0.015;r=0.428,P=0.036);the logistic analysis showed that FMD and AGEs were dependently associated with LVH (P=0.027,P=0.035),respectively. With the decreasing of FMD and increasing of AGEs, the odds ratio of morbidity of LVH were significantly increased.
Conclusion Endothelium-dependent Vasodilation impaired and large artery stiffness were regarded as the dependent risk factors of LVH.
Part five The study of heredity difference of elastin and matrix metalloproteinase gene polymorphism between Han patients and Uigur patients with isolated systolic hypertension
Objective To investigate the heredity difference of elastin and matrix metalloproteinase gene polymorphism(SNP) between Han patients and Uigur patients with isolated systolic hypertension(ISH).
Methods 358 Han patients with ISH were recruited from Nanfang hospital and 200 Uigur patients with ISH were recruited from People's Hospital of Xinjiang Uygur Autonomous Region. The genotypes of 4 SNPs were detected with LDR-PCR and the allele frequencies of each SNP in Han and Uigur patients with ISH were analyzed.
Results The frequencies of A allele of rs2071307 and rs34208922 and T allele of rs3918242 in Uigur patients with ISH were significantly higher than those in Han patients with ISH, however, there was no difference of 5A allele of rs3025058 between Han and Uigur patients with ISH. Furthermore, the frequencies of A allele of rs2071307 and rs34208922 were markedly increased with the increase of systolic blood pressure(P=0.0079, P=0.0040).
Conclusion Elastin gene polymorphism of rs2071307 and rs34208922 may be involved in the development of Han patients and Uigur patients with ISH.
收缩期高血压(ISH)是以收缩压增高和脉压差增大为特点的一种特殊类型高血压,常见于老年人,具有较高的致死、致残率,已成为人们研究的热点。随着我国人口老年化进程的加剧和人群疾病谱的变化,ISH患病率逐年增加。ISH作为原发性高血压的一种特殊亚型,发病机制复杂且远未阐明,目前认为是遗传因素和环境因素共同作用的结果。随着分子遗传学的发展,遗传因素在原发性高血压发病机制中的地位越来越受到重视,迄今为止被研究过的高血压候选基因至少有150种,它们涉及肾素-血管紧张素-醛固酮系统、交感神经系统、下丘脑-垂体轴、内皮素、利钠肽、激肽释放酶-激肽系统、类固醇激素、前列腺素、生长因子、激素、骨架蛋白、粘附分子、细胞内信使、脂质代谢、糖代谢、载脂蛋白、离子通道和转运体等,但各家报道结果不一致,还没有一个基因或基因变异被肯定与原发性高血压相关。原发性高血压等复杂性状疾病有以下共同特点：遗传模式未确定、遗传异质性强、外显率低、多个基因参与、单一基因的作用微弱等。虽然血压升高是高血压患者的共同表型,但患者的发病机制和与之相关的基因变异千差万别。因此对遗传异质性很强的高血压群体进行基因多态性分析,尤其当样本量不够大时,研究结果不一致就不足为奇了。我们认为在目前诊断的原发性高血压患者中可能包括了太多的亚型,笼而统之的研究难以获得结果。选择一些特殊的亚型进行研究可能成为阐明高血压发病机制的突破口。
动脉僵硬度增加、顺应性降低被认为是ISH典型的病理生理学特点,通过构建ISH模型人们发现促进动脉硬化的因素都可能导致ISH的发生发展。近来研究表明,弹性蛋白在大动脉中层中的含量和结构的改变都能导致动脉弹性降低,僵硬度增加。且国外众多研究还表明,弹性蛋白基因多态性及单体型与动脉僵硬度密切相关。Hanon等研究表明弹性蛋白SNP位点(rs2071307, exon16)与老年患者的弹性动脉的舒张性密切相关。Hiroyuki等认为弹性蛋白SNP位点(rs34208922,3'-UTR(+502)A)的基因变异可使弹性蛋白mRNA的表达下调,从而导致动脉壁弹性蛋白含量降低及功能的改变。Iwai等进一步证实该位点的变异与动脉僵硬度及收缩压升高密切相关。还有研究表明弹性蛋白基因多态性(rs41350445 and SNP rs41500150 in exon 5, rs34945509 in exon 20)可能在家族性颅内动脉瘤和蛛网膜下腔出血的发生、发展过程中起重要作用,其作用机制为以上SNP位点基因变异导致颅内动脉僵硬度增加,动脉顺应性降低所致。通过对弹性蛋白基因的这几个SNP位点的研究,我们也发现了rs2071307 (exon16)、rs34208922 (3'-UTR(+502)A)这两个SNP位点与ISH密切相关。
近年来,随着高血压病发病机制的深入研究,大动脉重构和功能的改变逐渐成为研究的热点。高血压病大动脉功能改变与重构是心血管病的独立预后危险因素。血管重构是指人血管容积、组成成分、构型和弹性等的改变。细胞外基质(ECM)的重组启动血管构型的变化,因此降解ECM最主要的酶--基质金属蛋白酶(MMPs)成为研究生理、病理性血管重构的焦点。ECM是由大分子构成的错综复杂的网络。构成ECM的大分子种类繁多,可归纳为四大类：胶原、糖蛋白、蛋白聚糖与透明质酸、弹性蛋白。基质金属蛋白酶(MMPs)是一组含能够降解ECM的蛋白酶,根据结构和底物特异性不同可分为5大类：间质胶原酶(MMP-1、MMP-8、MMP-13、MMP-18)、Ⅳ型胶原酶、明胶酶(MMP-2、MMP-9)、基质溶解素(MMP-3、MMP-7、MMP-10)、膜型(MMP-14、MMP-15、MMP-16)。MMPs活性增加及蛋白表达上调都可能导致血管内结构蛋白含量的改变及血管重构,同时MMPs的活性也能被组织抑制因子(TIMP)所抑制。由于MMPs具有导致血管重构的作用,MMPs被认定在某些心血管疾病(粥样斑块形成及破裂、心肌梗死及中风等)的发生发展及转归的过程中发挥重要作用。近年研究认为MMPs也与动脉硬化及血压升高密切相关。MMP-3是MMP家族中的一种关键酶,能影响其它基质金属酶的活性和作用,在保持大血管内基质稳态发挥着重要作用。其单核苷酸多态性的研究表明,SNP(rs3025058,5A/6A)与冠状动脉粥样硬化程度以及心肌梗死的危险性密切相关；体内及体外试验表明,血管组织内MMP-3 mRNA水平及蛋白水平在5A纯合子中表达最高,而在6A纯合子中表达最低,5A/6A杂合子居中。此外,5A纯合子的人群与5A/6A及6A纯合子相比具有动脉僵硬度显著增加和血压明显升高的特征。MMP-9是人们研究最多的一种基质金属蛋白酶,研究表明其活性及单核苷酸多态性不仅在冠心病的发生、发展中发挥重要作用,也与动脉硬化密切相关。Yamin等通过对MMP-2、MMP-9活性与ISH和动脉僵硬度的关系研究发现,MMP-9活性与ISH和动脉僵硬度密切相关,并推测MMP-9可能在ISH的发生发展过程中起主要作用。Lehoux等通过将大鼠颈动脉在压力不同的培养基中(10mmHg、80mmHg、150mmHg)放置3天后,测定MMP-2、MMP-9的活性,结果发现MMP-9在压力于150mmHg下较其它压力表达增强,且分别研究MMP-9缺陷及加入MMP-9活性的小鼠与血管僵硬度的关系,发现高压下血管僵硬度不再增加,认为高管腔内压力诱导的MMPs直接参与颈动脉僵硬度的增加过程,MMP-9在高血压病早期血管重构中起重要作用。最近有学者研究发现MMP-9的不同基因型对大动脉僵硬度作用不同。Medley等研究结果发现显示SNP (rs3918242, C-1562T)T纯合子及杂合子较C/C纯合子更能诱导proMMP-9的合成,增强MMP-9的活性,从而通过血管重构增加大动脉僵硬度,同时还发现T纯合子及杂合子人群与C/C纯合子人群相比动脉僵硬度显著增加,桡动脉及颈动脉收缩压、脉压显著升高。近来,Armstrong C等研究认为MMP-9 R279Q(rs17576)与颈动脉中层厚度(IMT)密切相关,MMP-1 A-519G(rs494379)、TIMP-3 T-1296C(rs5749511)在动脉硬化及血压升高方面具有重要作用,因此我们有理由认为MMP-1, MMP-3, MMP-9及TIMP-3可能为ISH的候选基因,在ISH的发生发展过程中起重要作用。
脉搏波传导速度(PWV)是评价动脉硬化的重要指标,研究表明收缩期高血压患者与双期高血压和健康人群相比PWV显著增高。晚期糖基化终产物(AGEs)近年来在评价动脉硬化方面的作用得到了进一步的肯定,研究认为AGEs与血管内结构蛋白通过桥接形成在动脉硬化的进程中发挥作用。血流介导的血管舒张功能(FMD)是评价内皮依赖性血管舒张功能的主要方式,研究表明,高血压患者普遍存在FMD受损的特点,并发现PWV越高FMD越低,FMD与PWV呈显著负相关。一氧化氮(NO)与内皮素-1(ET-1)分别为内皮衍生性的主要血管舒张和收缩因子,起到调节血管舒张和收缩的功能,在动脉硬化的发生发展过程中起主要作用。
我们假设MMP-1 rs494379 (A-519G), MMP-3 rs3025058 (5A/6A), MMP-9 rs17576 (R279Q), MMP-9 rs3918242 (C-1562T), TIMP-3 rs5749511 (T-1296C)5个SNP位点与收缩期高血压密切相关,并通过影响PWV、AGEs、FMD、NO、ET-1而发挥作用。
本课题旨在研究以上5个SNP位点与收缩期高血压的关系,并探讨它们与PWV、AGEs、FMD、NO、ET-1等的关系,从而揭示基质金属蛋白酶SNP的可能作用机制,为阐明收缩期高血压的发生发展提供科学依据。
第一章基质金属蛋白酶1,3,9及组织抑制因子3基因单核苷酸多态性与收缩期高血压关系的研究
目的研究基质金属蛋白酶1,3,9及组织抑制因子3基因单核苷酸多态性与收缩期高血压的关系。
方法从2005年1月至2008年12月选取广州、湛江、乌鲁木齐等三地503例收缩期高血压患者(ISH组),481例原发性高血压患者(EH组,非收缩期高血压)以及年龄相匹配的244例健康人群(NT组),采用连接酶检测反应(LDR-PCR)测定各患者基质金属蛋白酶1,3,9及组织抑制因子3基因5个SNP位点MMP-1rs494379 (A-519G), MMP-3 rs3025058 (5A/6A), MMP-9 rs17576 (R279Q), MMP-9 rs3918242(C-1562T), TIMP-3 rs5749511 (T-1296C)的基因表型,分析各SNP位点中的等位基因与收缩期高血压之间的关系,并进行单体型分析。
结果多元logistic回归分析结果显示,在控制年龄、甘油三酯、低密度脂蛋白等混杂因素的情况下,MMP-3基因SNP位点rs3025058(5A/6A)中5A等位基因和MMP-9基因SNP位点rs3918242(C-1562T)中的T等位基因与收缩期高血压密切相关(P<0.001,Pcorr＜0.003；P=-0.009,Pcorr=0.027)；其他各SNP位点中的等位基因与收缩期高血压无显著相关性；通过单体型分析还发现单体5A/G/C与原发性高血压相关,单体6A/A/T与收缩期高血压密切相关(Permutation p=0.0258; Permutation p=0.000002)。
结论MMP-3和MMP-9基因的变异可显著增加我国汉族人群发生收缩期高血压的危险性。
第二章基质金属蛋白酶3,9基因单核苷酸多态性与动脉硬化和血管内皮功能的关系
目的探讨基质金属蛋白酶3,9基因单核苷酸多态性与脉搏波传导速度(PWV)、晚期糖基化终产物(AGEs)和血流介导的血管舒张功能(FMD)、内皮素-1(ET-1)、一氧化氮(NO)的关系。
方法从2007年7月至2008年12月选取广州、湛江、乌鲁木齐等三地169例收缩期高血压患者(ISH组),134例原发性高血压患者(EH组,非收缩期高血压)以及年龄相匹配的71例健康人群(NT组),采用动脉硬化装置检测肱-踝脉搏波传导速度(baPWV),采用超声技术测定FMD,采用ELISA法检测患者外周血清中的AGEs、ET-1,并采用Griess反应法测定外周血中的NO浓度。分析各组人群中基质金属蛋白酶3,9基因rs3025058(5A/6A)、rs3918242(C-1562T)SNP位点中的不同基因表型个体间baPWV、FMD、AGEs、ET-1及NO之间的差异。
结果MMP-3基因SNP位点rs3025058(5A/6A)中5A/5A突变型纯合子患者的PWV显著高于5A/6A杂合子及6A/6A野生型纯合子患者(P<0.01),而MMP-3基因SNP位点rs3025058(5A/6A)中5A/5A突变型纯合子患者的FMD显著低于5A/6A杂合子及6A/6A野生型纯合子患者(P<0.01)；MMP-9基因SNP位点rs3918242(C-1562T)中T/T突变型纯合子患者的PWV显著高于C/T杂合子及T/T野生型纯合子患者(P<0.01),而MMP-9基因SNP位点rs3918242(C-1562T)中T/T突变型纯合子患者的FMD显著低于C/T杂合子及T/T野生型纯合子患者(P<0.01)。
结论MMP-3及MMP-9基因单核苷酸多态性与大动脉硬化和血管内皮功能障碍密切相关。
第三章收缩期高血压患者血清中晚期糖基化终产物与血管内皮功能的关系
目的探讨收缩期高血压患者血清中晚期糖基化终产物(AGEs)与血流介导的血管舒张功能(FMD)间的关系及其致内皮功能异常的作用。
方法选择收缩期高血压患者120例作为ISH组,原发性高血压患者(非收缩期高血压)120例作为DH组,年龄与之相匹配的健康人群70例作为NT组,采用SUN-8800动脉硬化检测仪测定PWV,超声技术测定FMD, ELISA检测受试者外周血清中AGEs和ET-1, Griess法测定外周血中NO含量。
结果收缩期高血压组的PWV、AGEs、ET-1显著高于原发性高血压组及健康对照组(P<0.05)；收缩期高血压组及原发性高血压组FMD、NO显著低于健康对照组(P<0.05),而FMD、NO在收缩期高血压组及原发性高血压组间无显著性差异；AGEs与cfPWV、ET-1呈显著正相关(r=0.525,P=0.000；r=0.863,P=0.000)；AGEs与FMD、NO呈显著负相关(r=-0.635,P=0.000；r=-0.669,P=0.000)；在控制年龄、收缩压、舒张压、血糖、总胆固醇、甘油三酯、低密度脂蛋白、高密度脂蛋白的情况下AGEs与cfPWV、FMD、NO及ET-1分别呈独立相关(Rsquare=0.513,P=0.000；R square=0.455,P=0.000；R square=0.453,P=0.000；R square=0.769,P=0.000)
结论AGEs是导致血管内皮功能异常的独立危险因素,可能在收缩期高血压的发生发展过程中起一定作用。
第四章单纯收缩期高血压患者血管内皮功能与左室肥厚的关系
目的探讨单纯收缩期高血压(ISH)患者血流依赖性血管舒张功能(FMD)与左心室肥厚的关系。
方法选择200例ISH患者,根据左心室重量指数分为左心室肥厚组(LVH,73例),非左心室肥厚组(NLVH,127例),同期选择年龄匹配的健康人群50例作为对照组,采用超声技术测定FMD,ELISA法检测受试者外周血清中晚期糖基化终产物(AGEs)和内皮素-1(ET-1),Griess法测定外周血中一氧化氮(NO)含量。
结果与NLVH组及对照组相比,LVH组FMD.NO均显著降低,而AGEs及ET-1均显著升高；左心室重量指数与AGEs.ET-1呈显著正相关(r=0.639,P=0.015；r=0.428,P=0.036),而与FMD及NO呈显著负相关(r=-0.718,P=0.003；r=-0.337,P=0.041)；FMD及AGEs与左心室肥厚呈独立相关(P=0.027,P=0.035)；随着FMD降低、AGEs的增加左室肥厚发病的危险性均显著增加。
结论血管内皮功能减退和大动脉硬化是ISH患者左心室肥厚的独立危险因素。
第五章弹性蛋白及基质金属蛋白酶基因单核苷酸多态性在维吾尔族和汉族收缩期高血压患者间的遗传差异研究
目的探讨弹性蛋白及基质金属蛋白酶基因单核苷酸多态性在不同种族收缩期高血压患者间的遗传差异。
方法选择358例汉族收缩期高血压患者作为HISH组,200例维吾尔族收缩期高血压患者作为VISH组,采用高温连接酶检测反应(LDR-PCR)进行基因表型检测,对比分析各SNP位点中的等位基因在不同种族人群众的分布频率差异。
结果弹性蛋白基因SNP位点rs2071307中的A等位基因,rs34208922中的A等位基因以及基质金属蛋白酶-9基因SNP位点rs3918242中的T等位基因在维吾尔族收缩期高血压患者的分布频率显著高于汉族收缩期高血压患者(P=0.000)；而基质金属蛋白酶-3基因SNP位点rs3025058中的5A等位基因在两组间的分布频率无显著性差异(P=0.112)。弹性蛋白基因SNP位点rs2071307和rs34208922中的A等位基因随着收缩压的升高,等位基因频率显著增加(P=0.0079,P=0.0040),而基质金属蛋白酶-3基因SNP位点rs3025058中的5A等位基因及基质金属蛋白酶-9 SNP位点rs3918242中的T等位基因在各段收缩压中的分布频率无显著性差异(P=0.5418,P=0.5046)。
结论弹性蛋白基因SNP位点rs2071307,rs34208922可能是汉族、维吾尔族收缩期高血压的易感基因。
Backgroud
Isolated systolic hypertension of the eldly was a subtype of essential hypertension and characteristiced by elevated systolic and pulse pressure, high mortality and high morbility. Even through, ISH has been an outcome of co-contribution of environment and inherit factors, unfortunately, the pathogenesis of ISH has not been fully understood. With the development of molecular genetics, the effect of inherit factor on the Essential Hypertension morbility has been emphasized. As yet,150 candidate genes for EH had been studied, which involved in renin-angiotensin-aldosterone system(RAAS), sympathetic nervous system(SNS), low-cerebral, ganglion-master, gland-axon, endothelin(ET), natriuretic peptide, KAL-kinin system, steroid hormone(STH), prostaglandin(PG), growth factor(GF), hormone, skeleton protein, adhesion molecule, intracellular messenger, lipide metabolism, glycometabolism, apolipoprotein(APO), ion channel, and so on. But no gene variant has been confirmed to be associated with EH. Owing to characteristic of the indefinite heredity model, high genetic heterogeneity, low penetrance, more genes participated, single gene effect feeble for the EH as some polygene diseases, and relatively low samples for the studies, it was all in the day's work that the studies arrived at different results. Because of the EH including some subtypes, it is difficult to get confirmedly information about the gene association with EH, and may be as a breakthrough to interpret EH pathogenesis to chose a certain subtype.
ISH was characterized by high artery stiffness and low artery compliance, it is reported that all the factors involved in promoting artery stiffness which might be lead to ISH. It had been confirmed that the change of structure and function of elastin located in the large artery media could caused artery stiffness, and some reports about the contributions of elastin to angio-development and cardiovascular diseases revoked our interest in studying elastin gene. a deletion involving 7q11.23 that results in hemizygosity of the elastin gene has been identified as the mechanism responsible for the Williams and Buren syndrome, which is characterized by supravalvular aortic stenosis, hypertension or peripheral stenoses. Li et al had reported that elastin is an essential determinant of arterial morphogenesis, the characterization of mice haploinsufficient for elastin (Eln+/-) revealed a role for elastin in the formation of vessel wall structure. The arteries of Eln+/-mice exhibited thinner elastic lamellae and an increased number of smooth muscle cell layers. Most interestingly, these identical changes have been observed in the arteries of patients with SVAS. D'Armiento J demonstrated that mice haploinsufficient for elastin develop structural changes in vessel walls similar to those seen in patients with mutations in the elastin gene. Due to mechanical changes in the vessel wall, these animals exhibit increased mean arterial pressures. The results evoke the possibility that alterations in elastin may contribute to the development of essential hypertension in patients.
Some studies had also reported that elastin gene polymorphisms were associated with artery stiffness, Hanon O et al identified the relationship between the Ser422Gly polymorphism of the elastin gene in exon 16(rs2071307) and the distensibility of elastic arteries 9. Interestingly, Iwai N et al revealed the association of the rs34208922 polymorphism with hypertension and pulse wave velocity. Furthermore, Akagawa H et al reported that SNP(rs34208922) is involved in the reduction of elastin mRNA transcripts in vitro and ex vivo. Recently, elastin has also been suggested to be a potential candidate gene for familial intracranial aneurysms (IAs) and subarachnoid hemorrhages (SAH), which we also found defects in the internal elastic lamina. As a result, ELN may be considered as a functional candidate gene for ISH. Our study has confirmed that SNP rs34208922 and SNP rs2071307 are associated with the ISH by affecting the artery stiffness.
Isolated systolic hypertension (ISH) is characterized by increased large artery stiffness and endothelial dysfunction. The factors that cause arterial stiffening and endothelial dysfunction are likely to be involved in the development of ISH. Large artery stiffness is influenced by the relative amounts of structural proteins (particularly elastin and collagens) and by smooth muscle tone. The matrix metalloproteinases (MMPs) are a family of zinc-dependent enzymes with proteolytic activity against connective tissue proteins such as collagens, proteoglycans and elastin. Increased expression and activity of MMPs has been identified in the change of relative amounts of structural proteins and vascular remodeling. Also, the activity of MMPs is influenced by tissue inhibitors of MMP (TIMP). In addition, there is a "functional" regulation of conduit artery stiffness by smooth muscle tone, which is influenced by circulating and endothelium-derived vasoactive mediators, including nitric oxide (NO) and endothelin-1(ET-1).
Due to their major influence in vascular remodeling, MMPs have been confirmed to play an important role in the pathogenesis and prognosis of cardiovascular (CV) diseases, including atherosclerotic plaque progression, myocardial infarction and strokes. Furthermore, studies have demonstrated that MMPs gene polymorphisms are associated with artery stiffness and high blood pressure. MMP-3 plays a pivotal role in large artery matrix homeostasis; Moreover, MMP-3 can activate several other matrix metalloproteinases. This versatile enzyme is believed to play important roles in vascular and cardiac matrix remodeling. Clinical investigations have shown that MMP-3 gene polymorphisms (5A/6A) are associated with coronary atherosclerosis and risk of myocardial infarction. Additionally, MMP-3 mRNA and protein level studies from ex vivo tissue, including vascular tissue from individuals of different genotypes for the 5A/6A polymorphism(rs3025058), showed that MMP-3 expression levels are highest in 5A homozygotes, intermediate in heterozygotes and lowest in 6A homozygotes. Furthermore, individuals with 5A allele homozygotes have increased large artery stiffness and higher blood pressure compared with 5A/6A heterozygotes and 6A homozygotes. In agreement, plasma concentrations and different genotypes for the-1562 C>T polymorphism(rs3918242) of MMP-9 are not only associated with the pathogenesis of coronary disease and prognosis of patients with cardiovascular disease, but also these T-1562 allele carriers have significantly greater aortic stiffness and higher brachial systolic and pulse pressure, in addition to carotid systolic and pulse pressure. Yasmin et al demonstrated that MMP-9 levels are related to aortic stiffness, not only in ISH patients, but also in younger and healthier individuals. Furthermore, studies have revealed the MMP-9 polymorphism (-1562 C/T) seems to play a key role in the early stages of hypertensive vascular remodeling and the process of large artery stiffening. Armstrong et al revealed that MMP-9 R279Q(rs17576) is associated with internal carotid artery bulb IMT, while MMP-1 A-519G(rs494379), TIMP-3 T-1296C (rs5749511) are significantly associated with hypertension and artery stiffness. As a result, MMP-1, MMP-3, MMP-9 and TIMP-3 genes may be considered as functional candidate genes for ISH.
Pulse wave velocity (PWV) is a known marker of arterial stiffness and defined as the speed in which the pulse wave travels along the length of an artery. Recently, a role for advanced glycation end products (AGEs) in the development of arterial stiffening has been suggested, in that the resultant cross-bridge formation between AGEs and structural proteins leads to increased arterial stiffness in the model of hypertension. Endothelial function, defined as flow mediated dilatation (FMD), is estimated as the percentage increase in vessel diameter from baseline conditions to maximum vessel diameter during hyperaemia and used as a measure of endothelium-dependent vasodilatation. Clinical investigation has demonstrated the presence of impaired endothelium-dependent vasodilation in patients with hypertension as flow-mediated dilatation is inversely correlated with PWV. Nitric oxide (NO) and endothelin-1 (ET-1), the major endothelium-derived relaxing and contracting factors that regulate endothelium-dependent vasodilation, are involved in the pathogenesis of artery stiffness and hypertension.
We hypothesized that MMP-1, MMP-3, MMP-9 and TIMP-3 genes polymorphism would be involved in the development of ISH by affecting PWV, FMD, plasma AGEs, ET-1 or NO. The aim of this study was to test these hypotheses in a group of subjects with ISH, EH subjects(no ISH) and age-matched normotensive control(NT).
Part one Associations of MMP1,3,9 and TIMP3 Genes Polymorphism with Isolated Systolic Hypertension in Chinese Han Population
Objective To investigate the relationship of MMP1,3,9 and TIMP3 genes polymorphism with isolated systolic hypertension in Chinese Han population.
Methods and results We identified the genotype of the genes in 503 patients with isolated systolic hypertension,481 essential hypertension patients with elevated diastolic blood pressure and 244 age-matched normotensive controls for 5 SNPs among the participants. Multinomial logistic analyses showed that the 5A allele of rs3025058(5A/6A) in MMP3 and the T allele of rs3918242(C-1562T) in MMP9 were significantly associated with isolated systolic hypertension after adjusted by age, triglyceride, low-density lipoprotein (P< 0.001,Pcorr< 0.003;P=0.009, Pcorr=0.027). The 5A/G/C was associated with essential hypertension and 6A/A/T haplotypes were significantly associated with isolated systolic hypertension (Permutation P=0.0258; Permutation P=0.000002). Conclusion MMP3 and MMP9 genes variant seem to contribute to the development of isolated systolic hypertension
Part two Association of Polymorphisms of matrix metalloproteinasesl,3,9 Gene with artery stiffness and endothelial function in Chinese Han Patients with Isolated Systolic Hypertension
Objective To investigate the relationship of polymorphisms of matrix metalloproteinasesl,3,9 gene with pulse wave velocity(PWV), advanced glycation end products(AGEs), flow mediated dilatation(FMD), endothelin-1(ET-1) and nitric oxide(NO) in Chinese Han patients with isolated systolic hypertension.
Methods We identified the genotype of the genes in 169 patients with isolated systolic hypertension,134 essential hypertension patients with elevated diastolic blood pressure and 71 age-matched normotensive controls whom recruited from July 2007 to December 2008 for 2 SNPs and detected the brachial-ankle pulse wave velocity, advanced glycation end products, flow-mediated dilatation, endothelin-1 and nitric oxide among the participants.
Results The baPWV, AGEs and ET-1 in ISH patients were significantly higher compared with EH patients and NT controls(P<0.01, Pcorr<0.05), the FMD and NO in ISH patients and EH patients were markedly lower than NT controls(P<0.01, Pcorr<0.05), although FMD and NO in ISH patients were not significantly different with EH patients. The baPWV of different genotypes for the 5 A/6 A and C-1562T polymorphisms were significantly highest in 5A or T homozygotes, intermediate in heterozygotes and lowest in 6A or C homozygotes(P<0.01, Pcorr<0.05).By contrast, the FMD and NO were markedly lowest in 5A·or T homozygotes, intermediate in heterozygotes and highest in 6A or C homozygotes (P<0.01, Pcorr<0.05), however, there were no difference for AGEs and ET-1 in different genotype of 5A/6A and C-1562T polymorphisms.
Conclusion MMP3 and MMP9 genes variant seem to contribute to the development of isolated systolic hypertension by affecting arterial stiffness and endothelial function.
Part three The Correlation of AGEs and Vascular Function in Patients with Isolated Systolic Hypertension
Objective To investigate the correlation of advanced glycation end products(AGEs) with flow-mediated diavasoculation(FMD) and the effects of AGEs on endothelium dysfunction in patients with isolated systolic hypertension.
Methods Overall,310 subjects were enrolled in this study,120 patients with isolated systolic hypertension(ISH),120 patients with essential hypertension (DH) and 70 age-matched NT(normotension control) subjects. All of them were detected pulse wave velocity(PWV) and FMD, and the serum concentration of AGEs, ET-1 were measured by ELISA, and NO by Griess'method.
Results The PWV, AGEs and ET-1 were significantly higher in ISH patients compared with NT controls and DH patients, however, the FMD and NO in ISH patients and DH patients were markedly lower than those in NT controls. AGEs was significantly positively correlated with PWV and ET-1(r=0.525,P=0.000; r=0.863,P=0.000),but negatively correlated with FMD and NO(r=-0.635,P=0.000; r=-0.669,P=0.000);furthermore, multiple linear regression analysis showed AGEs, cfPWV were risk factors predisposed for FMD.
Conclusion AGEs was the independent risk factor of endothelium dysfunction, and may be involved in the development of ISH.
Part four Association of Endothelium-dependent Vasodilation and Left Ventricular Hypertrophy in patients with isolated systolic hypertension
Objective To investigate the correlation of endothelium-dependent vasodilation and left ventricular hypertrophy in patients with isolated systolic hypertension.
Methods Overall,250 subjects were enrolled in this study,73 isolated systolic hypertension patients (ISH) with left ventricular hypertrophy,127 ISH patients without left ventricular hypertrophy and 50 age-matched NT(normotension control) subjects according to LVMI. All of them were detected FMD by echocardiography, and the serum concentration of AGEs, ET-1 were measured by ELISA, and NO by Griess reaction.
Results The FMD and NO in ISH patients with left ventricular hypertrophy were significantly decreased(P<0.01), however, the AGEs and ET-1 were markedly increased(P<0.01); Correlation analysis showed that LVMI were negatively correlated with FMD and NO (r=-0.718,P=0.003;r=-0.337,P=0.041), and positively correlated with AGEs and ET-1(r=0.639,.P=0.015;r=0.428,P=0.036);the logistic analysis showed that FMD and AGEs were dependently associated with LVH (P=0.027,P=0.035),respectively. With the decreasing of FMD and increasing of AGEs, the odds ratio of morbidity of LVH were significantly increased.
Conclusion Endothelium-dependent Vasodilation impaired and large artery stiffness were regarded as the dependent risk factors of LVH.
Part five The study of heredity difference of elastin and matrix metalloproteinase gene polymorphism between Han patients and Uigur patients with isolated systolic hypertension
Objective To investigate the heredity difference of elastin and matrix metalloproteinase gene polymorphism(SNP) between Han patients and Uigur patients with isolated systolic hypertension(ISH).
Methods 358 Han patients with ISH were recruited from Nanfang hospital and 200 Uigur patients with ISH were recruited from People's Hospital of Xinjiang Uygur Autonomous Region. The genotypes of 4 SNPs were detected with LDR-PCR and the allele frequencies of each SNP in Han and Uigur patients with ISH were analyzed.
Results The frequencies of A allele of rs2071307 and rs34208922 and T allele of rs3918242 in Uigur patients with ISH were significantly higher than those in Han patients with ISH, however, there was no difference of 5A allele of rs3025058 between Han and Uigur patients with ISH. Furthermore, the frequencies of A allele of rs2071307 and rs34208922 were markedly increased with the increase of systolic blood pressure(P=0.0079, P=0.0040).
Conclusion Elastin gene polymorphism of rs2071307 and rs34208922 may be involved in the development of Han patients and Uigur patients with ISH.
引文
[1]中国高血压防治指南起草委员会.2004年中国高血压防治指南(实用本).中华心血管病杂志,2004,32：1060-1064.
[2]Guidelines committee.2003 European society of hypertension-European society of cardiology guidelines for the management of arterial hypertension. J Hypertens,2003,21:1011-1053.
[3]Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. JAMA,2003,289:2560-2572.
[4]Franklin SS, Jacobs MJ, Wong ND, et al. Predominance of isolated systolic hypertension among middle-aged and elderly us hypertensives:analysis based on national health and nutrition examination survey(NHANES)III. Hypertension, 2001,37:869-874.
[5]Blacher J, Safar ME. Large-artery stiffness, hypertension and cardiovascular risk in older patients. Nature Clin Pract Cardiovasc Med,2005,2:450-455.
[6]Izzo JL Jr. Arterial stiffness and the systolic hypertension syndrome. Curr Opin Cardiol,2004,19:341-352.
[7]朱鼎良.我国高血压基因研究十年回顾和几点建议.中华心血管病杂志,2005，33：585-587.
[8]朱鼎良.开展高质量的高血压基因多态性关联研究.高血压杂志,2004,12：2-3.
[9]Doris PA, Fornage M. The transcribed genome and the heritable basis of essential hypertension. Cardiovasc Toxicol,2005,5:95-108.
[10]London GM, Marchais SJ, Guerin AP, et al. Arterial stiffness:pathophysiology and clinical impact. Clin Exp Hypertens,2004,26:689-699.
[11]Lakatta EG. Arterial and cardiac aging:major shareholders in cardiovascular disease enterprises. Part III:cellular and molecular cluesmto heart and arterial Aging. Ciculation,2003,107:490-497.
[12]Laurent S, Boutouyrie P, Lacolley P. Structural and genetic bases of arterial stiffness. Hypertension,2005,45:1050-1055.
[13]Hanon O, Luong V, Mourad JJ, et al. Aging, carotid artery distensibility, and the Ser422Gly elastin gene polymorphism in humans. Hypertension,2001,38: 1185-1189.
[14]Akagawa H, Tajima A, Sakamoto Y, et al. A haplotype spanning two genes, ELN and LIMK1, decreases their transcripts and confers susceptibility to intracranial aneurysms. Human Molecular Genetics,2006,15:1722-1734.
[15]Iwai N, Kajimoto K, Kokubo Y, et al. Extensive genetic analysis of 10 Candidate genes for hypertension in Japanese. Hypertension,2006,48: 901-907.
[16]Farnham JM, Camp NJ, Neuhausen SL, et al. Confirmation of chromosome 7q11 locus for predisposition to intracranial aneurysm. Hum Genet,2004,114: 250-255.
[17]Onda H, Kasuya H, Yoneyama T, et al. Genome wide-linkage and haplotype-association studies map intracranial aneurysm to chromosome 7qll. Am J Hum Genet,2001,69:804-819.
[18]Ruigrok YM, Seitz U, Wolterink S, et al.. Association of polymorphisms and haplotypes in the elastin gene in Dutch patients with sporadic aneurysmal subarachnoid hemorrhage. Stroke,2004,35:2064-2068.
[19]Deng L, Huang R, Xu DL, et al. A study on polymorphisms of elastin gene in Chinese Han patients with isolated systolic hypertension. Am J Hypertens,2009, 22:656-662.
[20]Opdenakker G, Van den Steen PE, Dubois B, et al. Gelatinase B functions as regulator and effector in leukocyte biology. J Leukoc Biol,2001,69:851-859.
[21]Godin D, Ivan E, Johnson C, et al. Remodeling of carotid artery is associated with increased expression of matrix metalloproteinases in mouse blood flow cessation model. Circulation,2000,102:2861-2866.
[22]Ye S, Eriksson P, Hamsten A, et al. Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem,1996,271:13055-13060.
[23]Tan J, Hua Q, Xing X, et al. Impact of the metalloproteinase-9/tissue inhibitor of metalloproteinase-1 system on large arterial stiffness in patients with essential hypertension. Hypertens Res,2007,30:959-963.
[24]Abilleira S, Bevan S, Markus HS. The role of genetic variants of matrix metalloproteinases in coronary and carotid atherosclerosis. J Med Genet,2006, 43:897-901.
[25]Blankenberg S, Rupprecht HJ, Poirier O, et al. Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation,2003,107:1579-1585.
[26]Yasmin, McEniery CM, O'Shaughnessy KM, et al. Variation in the human matrix metalloproteinase-9 gene is associated with arterial stiffness in healthy individuals. Arterioscler Thromb Vasc Biol,2006,26:1799-1805.
[27]Beilby JP, Chapman CM, Palmer LJ, et al. Stromelysin-1 (MMP-3) gene 5A/6A promoter polymorphism is associated with blood pressure in a community population. J Hypertens,2005,23:537-542.
[28]Beyzade S, Zhang S, Wong YK, et al. Influences of matrix metalloproteinase-3 gene variation on extent of coronary atherosclerosis and risk of myocardial infarction. J Am Coll Cardiol,2003,41:2130-2137.
[29]Medley TL., Kingwell BA., Gatzka CD., et al. Matrix metalloproteinase-3 genotype contributes to age-related aortic stiffening through modulation of gene and protein expression. Circ Res,2003,92:1254-1261.
[30]Higo S, Uematsu M, Yamagishi M, et al. Elevation of plasma matrix metalloproteinase-9 in the culprit coronary artery in patients with acute myocardial infarction:clinical evidence from distal protection. Circ J,2005,69: 1180-1185.
[31]Morgan AR, Zhang B, Tapper W, et al. Haplotypic analysis of the MMP-9 gene in relation to coronary artery disease. J Mol Med,2003,81:321-326.
[32]Yasmin, Sharon Wallace, Carmel M, et al. Matrix metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness. Arterioscler Thromb Vase Biol,2005,25:372-378.
[33]Lehoux S, Lemarie CA,Espostio B, et al. Pressure-induced matrix metalloprote-inase-9 contributes to early hypertensive remodeling. Circulation,2004,109: 1041-1047.
[34]Zhou S, Feely J, Spiers JP, et al. Matrix metalloproteinase-9 polymorphism contributes to blood pressure and arterial stiffness in essential hypertension. J Hum Hypertens,2007,21:861-867.
[35]Medley TL, Cole TJ, Dart AM, et al. Matrix metalloproteinase-9 genotype luences large artery stiffness through effects on aortic gene and protein expression. Arterioscler Thromb Vase Biol,2004,24:1479-1484.
[36]Armstrong C, Abilleira S, Sitzer M, et al. Polymorphisms in MMP family and TIMP genes and carotid artery intima-media thickness. Stroke,2007,38: 2895-2899.
[37]Oliver JJ, Webb DJ. Noninvasive assessment of arterial stiffness and risk of atherosclerotic events. Arterioscler Thromb Vasc Biol,2003,23:554-566.
[38]Semba RD, Najjar SS, Sun K, et al. Serum carboxymethyl-lysine, an advanced glycation end product, is associated with increased aortic pulse wave velocity in adults. Am J Hypertens,2009,2:74-79.
[39]McNulty M, Mahmud A, Feely J. Advanced glycation end-products and arterial stiffness in hypertension. Am J Hypertens,2007,20:242-247.
[40]Bots ML, Westerink J, Rabelink TJ, et al. Assessment of flow-mediated vasodilatation (FMD) of the brachial artery:effects of technical aspects of the FMD measurement on the FMD response. Eur Heart J,2005,26:363-368.
[41]Martin C, Cameron J, McGrath B. Mechanical and circulating biomarkers in isolated clinic hypertension. Clin Exp Pharmacol Physiol,2008,35:402-408.
[42]Cockcroft JR. Exploring vascular benefits of endothelium-derived nitric oxide. Am J Hypertens.,2005,18:177S-18.
[1]中国高血压防治指南起草委员会.2004年中国高血压防治指南(实用本).中华心血管病杂志,2004,32：1060-1064.
[2]Guidelines committee.2003 European society of hypertension-European society of cardiology guidelines for the management of arterial hypertension. J Hypertens,2003,21:1011-1053.
[3]Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. JAMA,2003,289:2560-2572.
[4]Franklin SS, Jacobs MJ, Wong ND, et al. Predominance of isolated systolic hypertension among middle-aged and elderly us hypertensives:analysis based on national health and nutrition examination survey(NHANES)III. Hypertension, 2001,37:869-874.
[5]Blacher J, Safar ME. Large-artery stiffness, hypertension and cardiovascular risk in older patients. Nature Clin Pract Cardiovasc Med,2005,2:450-455.
[6]Izzo JL Jr. Arterial stiffness and the systolic hypertension syndrome. Curr Opin Cardiol,2004,19:341-352.
[7]朱鼎良.我国高血压基因研究十年回顾和几点建议.中华心血管病杂志,2005,33(7)：585-587.
[8]朱鼎良.开展高质量的高血压基因多态性关联研究.高血压杂志,2004,122-3.
[9]Doris PA, Fornage M. The transcribed genome and the heritable basis of essential hypertension. Cardiovasc Toxicol,2005,5:95-108.
[10]London GM, Marchais SJ, Guerin AP, et al. Arterial stiffness:pathophysiology and clinical impact. Clin Exp Hypertens,2004,26:689-699.
[11]Lakatta EG. Arterial and cardiac aging:major shareholders in cardiovascular disease enterprises. Part III:cellular and molecular cluesmto heart and arterial Aging. Ciculation,2003,107:490-497.
[12]Laurent S, Boutouyrie P, Lacolley P. Structural and genetic bases of arterial stiffness. Hypertension,2005,45:1050-1055.
[13]Wallace SM, Yasmin, McEniery CM, et al. Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction. Hypertension,2007,50:228-233.
[14]Opdenakker G, Van den Steen PE, Dubois B, et al. Gelatinase B functions as regulator and effector in leukocyte biology. J Leukoc Biol,2001,69:851-859.
[15]Godin D, Ivan E, Johnson C, et al. Remodeling of carotid artery is associated with increased expression of matrix metalloproteinases in mouse blood flow cessation model. Circulation,2000,102:2861-2866.
[16]Ye S, Eriksson P, Hamsten A, et al. Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem,1996,271: 13055-13060.
[17]Tan J, Hua Q, Xing X, et al. Impact of the metalloproteinase-9/tissue inhibitor of metalloproteinase-1 system on large arterial stiffness in patients with essential hypertension. Hypertens Res,2007,30:959-963.
[18]Abilleira S, Bevan S, Markus HS. The role of genetic variants of matrix metalloproteinases in coronary and carotid atherosclerosis. J Med Genet,2006, 43:897-901.
[19]Blankenberg S, Rupprecht HJ, Poirier O, et al. Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation,2003,107:1579-1585.
[20]Yasmin, McEniery CM, O'Shaughnessy KM, et al. Variation in the human matrix metalloproteinase-9 gene is associated with arterial stiffness in healthy individuals. Arterioscler Thromb Vasc Biol,2006,26:1799-1805.
[21]Beilby JP, Chapman CM, Palmer LJ, et al. Stromelysin-1 (MMP-3) gene 5A/6A promoter polymorphism is associated with blood pressure in a community population. J Hypertens,2005,23:537-542.
[22]Beyzade S, Zhang S, Wong YK, et al. Influences of matrix metalloproteinase-3 gene variation on extent of coronary atherosclerosis and risk of myocardial infarction. J Am Coll Cardiol,2003,41:2130-2137.
[23]Medley TL, Kingwell BA, Gatzka CD, et al. Matrix metalloproteinase-3 genotype contributes to age-related aortic stiffening through modulation of gene and protein expression. Circ Res,2003,92:1254-1261.
[24]Higo S, Uematsu M, Yamagishi M, et al. Elevation of plasma matrix metalloproteinase-9 in the culprit coronary artery in patients with acute myocardial infarction:clinical evidence from distal protection. Circ J,2005,69: 1180-1185.
[25]Morgan AR, Zhang B, Tapper W, et al. Haplotypic analysis of the MMP-9 gene in relation to coronary artery disease. J Mol Med,2003,81:321-326.
[26]Yasmin, Sharon Wallace, Carmel M, et al. Matrix metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness. Arterioscler Thromb Vasc Biol,2005,25:372-378.
[27]Lehoux S, Lemarie CA, Espostio B, et al. Pressure-induced matrix metalloproteinase-9 contributes to early hypertensive remodeling. Circulation, 2004,109:1041-1047.
[28]Zhou S, Feely J, Spiers JP, et al. Matrix metalloproteinase-9 polymorphism contributes to blood pressure and arterial stiffness in essential hypertension. J Hum Hypertens,2007,21:861-867.
[29]Medley TL, Cole TJ, Dart AM, et al. Matrix metalloproteinase-9 genotype luences large artery stiffness through effects on aortic gene and protein expression. Arterioscler Thromb Vasc Biol,2004,24:1479-1484.
[30]Armstrong C, Abilleira S, Sitzer M, et al. Polymorphisms in MMP family and TIMP genes and carotid artery intima-media thickness. Stroke,2007,38: 2895-2899.
[31]Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure:the JNC 7 report. JAMA,2003,289:2560-2572.
[32]European Society of Hypertension-European Society of Cardiology Guidelines Committee.2003 European Society of Hypertension-Eu isolated systolic hypertension among middle-aged and elderly US hypertensives:analysis based on National Health and Nutrition Examination Survey (NHANES) III. Hypertension,2001,37:869-874.
[33]Primatesta P, Poulter NR. Hypertension management and control among English adults aged 65 years and older in 2000 and 2001. J Hypertens,2004,22: 1093-1098.
[34]Safar ME. Hypothesis on isolated systolic hypertension in the elderly. J Hum Hypertens,1999,13:813-815.
[35]Sethi AA, Nordestgaard BG, Agerholm-Larsen B, et al. Angiotensinogen polymorphisms and elevated blood pressure in the general population:the Copenhagen City Heart Study. Hypertension,2001,37:875-881.
[36]Jackson ZS, Gotlieb A I, Langille BL. Wall tissue remodeling regulates longitudinal tension in arteries. Circ Res,2002,90:918-925.
[37]Wang MY, Lakatta EG. Altered regulation of matrix metalloproteinase 2 in aortic remodeling during aging. Hypertension,2002,39:865-874.
[38]Wang M, Zhang J, Sp inetti G, et al. Angiotensin II activates matrix metallop-roteninase type II and mimics age-associated carotid arterial remodeling in young rats. Am J Pathol,2005,167:1429-1442.
[39]Rodriguez-Vita J, Ruiz Ortega M, Ruperez M, et al. Endothelin-1, via ETA receptor and independently of transforming growth factor beta, increases the connective tissue growth factor in vascular smooth muscle cells. Circ Res,2005, 97:125-134.
[40]Shofuda T, Shofuda K, FerriN, et al. Cleavage of focal adhesion kinase in vascular smooth muscle cells overexp ressingmembrane type matrixmetallop roteinases. Arterioscler Thromb Vasc B iol,2004,24:839-844.
[41]Filippov S, Koenig GC, Chun TH, et al. MMP2 matrix metalloproteinase directs arterialwall invasion and neointima formation by vascular smooth muscle cells. J Exp Med,2005,202:663-671.
[42]McEniery CM, Wallace S, Dakham Z, et al,Matrix metalloproteinas-9 (MMP-9),MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness. A rterioscler Thromb Vasc B iol,2005,25: 372-378.
[43]Medley TL, Kingwell BA, Gatzka CD, et al. Matrix metalloproteinase-3 genotype contributes to age-related aortic stiffening through modulation of gene and protein expression. Circ Res,2003,92:1254-1261.
[44]Ergul A, Portik Dobos V, Hutchinson J, et al. Downregulation of vascular matrix metalloproteinase inducer and activator proteins in hypertensive patients. Am J Hypertens,2004,17:775-782.
[45]Bouvet C, Gilbert LA, Girardot D, et al. Different involvement of extracellular matrix components in small and large arteries during chronic NO synthase inhibition. Hypertension,2005,45:432-437.
[46]Lepetit H, Eddahibi S, Fadel E, et al. Smoothmuscle cell matrix metallop-roteinnase in idiopathic pulmonary aterial hypertension. Eur Resp ir J,2005, 25:834-842.
[47]Defawe OD, Kenagy RD, Choi C, et al. MMP-9 regulates both positively andnegatively collagen gel contraction:a nonp roteolytic function of MMP-9.Cardiovasc Res,2005,66:402-409.
[48]Yasmin A, McEniery CM, Wallace S, et al. Matrix metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hyretension and arterial stiffness. Arterioscler Thromb Vasc Biol,2005,25 372-378.
[49]Dhingra R, Pencina MJ, Schrader P, et all. Relations of matrix remodeling biomarkers to blood pressure progression and incidence of hypertension in the community. Circulation,2009,119:1101-1107.
[50]Misra S, Fu AA, Puggioni A, et al. Increased shear stress with up regulation of VEGF-A and its recep tors and MMP-2, MMP-9, and TIMP-1 in venous stenosis of hemodialysis grafts. Am J Physiol Heart Circ Physiol,2008,294 H2219-2230.
[51]Walter ERA, Neetu T, Utpal S, et al. Inhibition of matrix metalloproteinase-9 reverses changes in vascular wall structure and function of thoracic aorta of Dah.salt-sensitive rats. FASEB J,2009,23:1017-1032.
[52]L i H, Simom H, Bocan TM, et al. MMP/TIMP expression in spontaneously hypertensive heart failure rats:the effect of ACEI and MMP-inhibition 1.Cardiovasc Res,2000,46:298-306.
[53]Derosa G, Angelo A, Ciccarelli L, et al. Matrix metallop roteinase-2,-9, and tissue inhibitor of metallop roteinase-1 in patientswith hypertension. Endothelium,2006,13:227-231.
[54]Heymans S, Schroen B,Vermeersch P, et al. Increased cardiac expression of tissue inhibitor of metallop roteinase-1 and tissue inhibitor of metallop roteinase-2 is related to cardiac fibrosis and dysfunction in the chronic pressure-overloaded human heart. Circulation,2005,112:1136-1144.
[55]Sakata Y, Yamamoto K, Mano T, et al. Activation of matrix metalloproteinases precedes left ventricular remodeling in hypertensive heart failure rats:its inhibitiion as a primary effect of angiotensin-conerting enzyme inhibitor. Circulation,2004,109:2143-2149.
[56]Saglam M, Karakaya O, Esen AM, et al. Contribution of plasma matrix metallop roteinases to development of left ventricular hypertrophy and diastolic dysfunction in hypertensive subjects. Tohoku J Exp Med,2006,208:117-122.
[57]Reinhardt D, Sigusch HH, Hensse J, et al. Cardiac remodelling in end stage heart failure:up regulation of matrix metalloproteinase (MMP) irrespective of the underlying disease, and evidence for a direct inhibitory effect of ACE inhititors on MMP. Heart,2002,88:525-530.
[58]Williams RN, Parsons SL, Morris TM, et al. Inhibition of matrix metallop-roteinase activity and growth of gastric adenocarcinoma cells by an angiotensin conerting enzyme inhibitor in vitro and murine models. Eur J Surg Oncol, 2005,31:1042-1050.
[59]Bautista LE, Lopez, Jaramillo P, et al. Is C-reative protein an independent risk factor for essential hypertension. J Hypertens,2001,19:857-861.
[60]Bautista LE, Vera LM, Arenas IA, et al. Independent association between inflammatory markers (C-reactive protein, interleukin-6, and TNF-alpha) and essential hypertension. J Hum Hypertens,2005,19:149-154.
[61]Sesso HD, Buring JE, Rifai N, et al. C-reactive protein and the risk of developing hypertension. JAMA,2003,290:2945-2951.
[62]Das UN. Metabolic syndrome X:an inflammatory condition?. Curr Hypertens Rep,2004,6:66-73.
[63]Solini A, Santini E, Passaro A, et al. Family history of hypertension, anthropometric parameters and markers of early atherosclerosis in young healthy individuals. J Hum Hypertens,2009,2:151-157.
[64]Palei AC, Sandrim VC, Cavalli RC, et al. Comparative assessment of matrix metalloproteinase (MMP)-2 and MMP-9, and their inhibitors, tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 in preeclamp sia and gestational hyertension. Clin Biochem,2008,41:875-880.
[65]Djuric T, Zivkovic M, Radak D, et al. Association of MMP-35A/6A gene polymorphism with susceptibility to carotid atherosclerosis. Clin Biochem,2008, 41:1326-1329.
[66]康照梅,牟善初,张晓英,等MMP-2、MMP-3、TIMP-1及氯沙坦与氨氯地平在老年前期自发性高血压大鼠肾硬化中的作用及其机理探讨.中华老年多器官疾病杂志,2003,2：211-215.
[1]Najjar SS, Scuteri A, Lakatta EG. A rterial aging. Is it an immutable cardiovascular risk factor?. Hypertension,2005,46:454-462.
[2]Safar ME. Systolic blood pressure, pulse pressure and arterial stiffness as cardiovascular risk factors. Curr Op in Nephrol Hypertens,2001,10:257-261.
[3]Laurent S, Boutouyrie P, Lacolley P. Structural and genetic bases of arterial stiffness.Hypertension,2005,45:1050-1055.
[4]Izzo JL Jr. Arterial stiffness and the systolic hypertension syndrome. Curr Opin Cardiol,2004,19:341-352.
[5]Yambe M, Tomiyama H, Yamada J, et al. Arterial stiffness and progression to hypertension in Japanese male subjects with high normal blood pressure. J Hypertens,2007,25:87-93.
[6]Beltran A, McVeigh G, Morgan D, et al. Arterial compliance abnormalities in isolated systolic hypertension. Am J Hypertens,2001,14:1007-1011.
[7]Wallace SM, Yasmin, McEniery CM, et al. Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction. Hypertension,2007,50:228-233.
[8]Newsholme P, Homem De, Bittencourt PI, et al. Exercise and possible molecular mechanisms of protection from vascular disease and diabetes:the central role of ROS and nitric oxide. Clin Sci,.2009,118:341-349.
[9]Beevers G, Lip GY, O'Brien E. ABC of hypertension:The pathophysiology of hypertension. BMJ,2001,14:912-916.
[10]Oliver JJ, Webb DJ. Noninvasive assessment of arterial stiffness and risk of atherosclerotic events. Arterioscler Thromb Vasc Biol,2003,23:554-566.
[11]Semba RD, Najjar SS, Sun K, et al. Serum carboxymethyl-lysine, an advanced glycation end product, is associated with increased aortic pulse wave velocity in adults. Am J Hypertens,2009,2:74-79.
[12]McNulty M, Mahmud A, Feely J. Advanced glycation end-products and arterial stiffness in hypertension. Am J Hypertens,2007,20:242-247.
[13]Bots ML, Westerink J, Rabelink TJ, et al. Assessment of flow-mediated vasodilatation (FMD) of the brachial artery:effects of technical aspects of the FMD measurement on the FMD response. Eur Heart J,2005,26:363-368.
[14]Martin C, Cameron J, McGrath B. Mechanical and circulating biomarkers in isolated clinic hypertension. Clin Exp Pharmacol Physiol,2008,35:402-408.
[15]Cockcroft JR. Exploring vascular benefits of endothelium-derived nitric oxide. Am J Hypertens,.2005,18:177S-183S.
[16]Cohn JN. Vascular wall function as a risk marker for cardiovascular disease. J Hypertens,1999,17:41-44.
[17]Giovanni de Simone, et al.Stroke volume/pulse pressure ratio and cardiovascular risk in artrial hypertension. Hypertension,1999,33:800-805.
[18]任军梅,王瑞英.老年高血压患者脉压与靶器官损害.心血管病学进展,2005,26：141-143.
[19]丁跃有,张维忠.高血压动脉弹性功能无创性评价.高血压杂志,2002,10：503-504.
[20]Goldwyn RM. Arterial pressure pulse contour analysis via a mechanical model for the clinical quanification of human vascular properties. IEEE Trans Biomed, 1967，14：11-17.
[21]丁跃有,张维忠.健康人与高血压患者动脉弹性功能比较.高血压杂志,2003,11：333-336.
[22]刘丽芳,谢晋湘.汉族人群中血压与动脉硬化关系的研究.中国循环杂志,2003,18：129-131.
[23]王炳和,相敬林.一种无创性测定桡动脉脉搏波速度的方法及影响脉搏波速度的因素.生物医学工程学杂志,2000,17：179-182.
[24]Asmar R, Topouchian J, et al. Assessment of arterial distensibility by antomatic pulse wave velocity measurement. Validation and clinical application studies. Hypertens,1995,26:485-490.
[25]Tomoki Shokawa, Minchinori Imazu, et al. Pulse wave velocity predicts cardiovascular mortality findings from the Hawaii-Los Angeles-Hiroshima Study. Circ J,2005,69:259-264.
[26]Naidu MU, Reddy BM, Yashmaina S, et al. Validity and reproducibility of arterial pulse wave velocity measummem using new device with oscillometric technique:a pilot study. Biomed Eng Online,2005,4:49.
[27]胡大一,马长生主编.心脏病学实践2007-新进展与临床案例.北京：人民卫生出版社,2007,10：311-319.
[28]Jadhav UM, Kadam NN. Non-invasive assessmem of arterial stiffness by pulse wave velocity correlates with endothelial dysfunction. Indian Heart J,2005,57: 226-232.
[29]Kochkina MS, Zateishchikov DA, Sidorenko BA. Measurement of arterial stiffness and its clinical value. Kardiologiia,2005,45:63-71.
[30]张志勉,胡利芳,梁济乐,等.老年高血压合并动脉粥样硬化患者主动脉僵硬度的临床研究.山东大学学报(医学版),2005,43：57-59.
[31]华琦,谭静,刘东霞,等.高血压病患者颈-股动脉和颈-桡动脉脉搏波速度改变及其影响因素.中华心血管病杂志,2005,33：1088-1091.
[32]谭静,华琦,邢绣荣,等.高血压病患者脉搏波速度与动态脉压的相关性研 究.首都医科大学学报,2007,28：101-103.
[33]Benetos A, Adamopoulos C, Bureau JM, et al. Determinants of accelerated progression of arterial stiffness in normotensive subjects and in treated hypertensive subjects over a year period. Circulation,2002,105:1202-1207.
[34]Protogerou A, Blacher J, Stergiou GS, et al. Blood pressure response under chronic antihypertensive drug therapy:the role of aortic stiffness in the REASON (Preterax in Regression of Arterial Stiffness in a Controlled Double-Blind)study. J Am Coil Cardiol,2009,53:445-451.
[35]张丽,黄晶,李祥嫒,等.高血压治疗前后PWV的相关性研究.重庆医科大学学报,2008,33：207-209.
[36]Soro-Paavonen A, Watson AM, Li J, et al. Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes. Diabetes.,2008,57:2461-2469.
[37]Yan SF, Ramasamy RH, Naka YF Glycation, et al. A scaffold for the macrovascular complications of diabetes and beyond. Circ Res,2003,93: 1159-1169.
[38]郭志坚,侯凡凡,张训,等.晚期糖基化终产物通过p38信号通路抑制内皮细胞合成一氧化氮的研究.中华医学杂志,2002,19：1328-1331.
[39]Wallace SM, Yasmin, McEniery CM, et al. Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction. Hypertension,2007,50:228-233.
[1]Zieman S J, Kass D A. Advanced glycation end products cross-linking in the cardiovascular system potential therapeutic target for cardiovascular disease. Drugs,2004,64:2459-2470.
[2]许顶立,刘艳玲,孟素荣,等.冠心病患者血清晚期糖基化终产物Nε-羧甲 基赖氨酸含量的变化.中华老年心脑血管病杂志,2000,2：161-163.
[3]Semba RD, Najjar SS, Sun K, et al. Serum carboxymethyl-lysine, an advanced glycation end product, is associated with increased aortic pulse wave velocity in adults. Am J Hypertens,2009,2:74-79.
[4]McNulty M, Mahmud A, Feely J. Advanced glycation end-products and arterial stiffness in hypertension. Am J Hypertens,2007,20:242-247.
[5]Wallace SM, Yasmin, McEniery CM, et al. Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction. Hypertension,2007,50:228-233.
[6]庞战军.Griess试剂法-自由基医学研究方法[M],北京,人民卫生出版社,224-226.
[7]Soro-Paavonen A, Watson AM, Li J, et al. Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes. Diabetes.,2008,57:2461-2469.
[8]Jandeleit-Dahm K, Cooper ME. The role of AGEs in cardiovascular disease. Curr Pharm Des,.2008,14:979-986.
[9]吴雅利,雷梦觉,刘秋玲,等.单纯收缩期高血压年龄与血管内皮功能对大动脉僵硬度的影响.中华高血压杂志,2008,16：704-706.
[10]Yan SF, Ramasamy RH, Naka YF Glycation, et al. A scaffold for the macrovascular complications of diabetes and beyond. Circ Res,2003,93: 1159-1169.
[11]郭志坚,侯凡凡,张训,等.晚期糖基化终产物通过p38信号通路抑制内皮细胞合成一氧化氮的研究.中华医学杂志,2002,19：1328-1331.
[1]Wachtell K,Okin PM,Olsen MH,et al.Regression of electrocardiographic left ventricular hypertrophy during antihypertensive therapy and reduction in sudden cardiac death:the LIFE Study. Circulation,2007,116:700-705.
[2]黄丽娟,谢良地,陈翠林,等.原发性高血压左室肥厚患者的血管内皮依赖性舒张功能.中华高血压杂志,2009,17：737-742.
[3]贺利平,赵兴胜,吴云.高血压左室肥厚与三种血管活性因子水平的相关性研究.中国心血管病研究,2008,6：346-348.
[4]宋涛,葛志明,巩会萍,等.原发性高血压左室肥厚患者动脉结构和功能改变的临床研究.中国超声医学杂志,2008,24：123-126.
[5]Devereux RB,Alonso DR,Lutas EM,et al. Echocardiographic assessment of left ventricular hypertrophy:comparison to necropsy findings. Am J Cardiol 1986,57:450-458.
[6]Wallace SM,Yasmin,McEniery CM,et al. Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction. Hypertension,2007,50:228-233.
[7]Bots ML,Westerink J,Rabelink TJ,et al. Assessment of flow-mediated vasodilatation (FMD) of the brachial artery:effects of technical aspects of the FMD measurement on the FMD response. Eur Heart J,2005,26:363-368.
[8]Xu JZ,Zhang Y,Wu SN,et al.Impaired endothelial function in hypertensive patients with target organ damage. J Hum Hypertens,2009,23:751-757.
[9]陈明,胡申江,张健,等.不同危险度的高血压病人血管内皮功能.高血压杂志,2006,14：257-260.
[10]Pechanova O,Kunes J,Dobesova Z,et al. N-acetylcysteine-induced increase of NO synthase activity in the brain of normotensive and hypertensive rats. J Physiol Pharmacol,2009,60:21-25.
[11]Lind L.Left ventricular mass is related to endothelium-dependent vasodilation in the forearm, but not in the brachial artery, in elderly subjects:the Prospective Investigation of the Vasculature in Uppsala Seniors study. J Hum Hypertens,2008,22:767-773.
[12]Aubin MC, Carrier M, Shi YF,et al. Role of probucol on endothelial dysfunction of epicardial coronary arteries associated with left ventricular hypertrophy. J Cardiovasc Pharmacol,2006,47:702-710.
[13]McNulty M,Mahmud A,Feely J. Advanced glycation end-products and arterial stiffness in hypertension. Am J Hypertens,2007,20:242-247.
[14]郭志坚,侯凡凡,张训,等.晚期糖基化终产物通过p38信号通路抑制内皮细胞合成一氧化氮的研究.中华医学杂志,2002,19：1328-1331.
[15]Yan SF,Ramasamy R,Schmidt AM,et al.Receptor for AGE (RAGE) and its ligands-cast into leading roles in diabetes and the inflammatory response. J Mol Med,2009,87:235-247.
[1]Deng L, Huang R, Chen Z, et al. A study on polymorphisms of elastin gene in Chinese Han patients with isolated systolic hypertension. Am J Hyperten,2009, 22:656-662.
[2]Xiao Z, Xiao J, Jiang Y, et al. A novel method based on ligase detection reaction for low abundant YIDD mutants detection in hepatitis B virus. Hepatol Res, 2006,34:150-155.
[3]Wallace SM, Yasmin, McEniery CM, et al. Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction. Hypertension,2007,50:228-233.
[4]文灿,朱星红.动脉弹性蛋白的研究进展.中国病理生理杂志,2001,17：1029-1033.
[5]Tsoporis J, Keeley FW, Lee RMKW, et al. Arterial vasodilation and vascular connective tissue changes in spontaneously hypertensive rats. J Cardiovas Pharmac,1998,31:960-962.
[6]Godin D, Ivan E, Johnson C, et al. Remodeling of carotid artery is associated with increased expression of matrix metalloproteinases in mouse blood flow cessation model. Circulation,2000,102:2861-2866.
[7]Ye S, Eriksson P, Hamsten A, et al. Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem,1996,271:13055-13060.
[8]Hanon O, Luong V, Mourad JJ, et al. Aging, carotid artery distensibility, and the Ser422Gly elastin gene polymorphism in humans. Hypertension,2001,38: 1185-1189.
[9]Akagawa H, Tajima A, Sakamoto Y, et al. A haplotype spanning two genes, ELN and LIMK1, decreases their transcripts and confers susceptibility to intracranial aneurysms. Human Molecular Genetics,2006,15:1722-1734.
[10]Iwai N, Kajimoto K, Kokubo Y, et al. Extensive Genetic analysis of 10 Candidate genes for hypertension in Japanese. Hypertension,2006,48: 901-907.
[11]Medley TL, Kingwell BA, Gatzka CD, et al. Matrix metalloproteinase-3 genotype contributes to age-related aortic stiffening through modulation of gene and protein expression. Circ Res,2003,92:1254-1261.
[12]Beyzade S, Zhang S, Wong YK, et al. Influences of matrix metalloproteinase-3 gene variation on extent of coronary atherosclerosis and risk of myocardial infarction. J Am Coll Cardiol,2003,41:2130-2137.
[13]Beilby JP, Chapman CM, Palmer LJ, et al. Stromelysin-1 (MMP-3) gene 5A/6A promoter polymorphism is associated with blood pressure in a community population. J Hypertens,2005,23:537-542.
[14]Higo S, Uematsu M, Yamagishi M, et al. Elevation of plasma matrix metalloproteinase-9 in the culprit coronary artery in patients with acute myocardial infarction:clinical evidence from distal protection. Circ J,2005,69: 1180-1185.
[15]Morgan AR, Zhang B, Tapper W, et al. Haplotypic analysis of the MMP-9 gene in relation to coronary artery disease. J Mol Med,2003,81:321-326.
[16]Medley TL, Cole TJ, Dart AM, et al. Matrix metalloproteinase-9 genotype luences large artery stiffness through effects on aortic gene and protein expression. Arterioscler Thromb Vasc Biol,2004,24:1479-1484.
[17]Yasmin, McEniery CM, Wallace S, et al. Matrix metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness. Arterioscler Thromb Vasc Biol,2005,25:372.
[1]Essalihi R, Dao HH, Yamaguchi N, Moreau P.A new model of isolated systolic hypertension induced by chronic warfarin and vitamin K1 treatment. Am J Hypertens 2003;16:103-110.
[2]Essalihi R, Dao HH, Yamaguchi N, Moreau P. A new model of isolated systolic hypertension induced by chronic warfarin and vitamin K1 treatment. Am J Hypertens 2003;16:103-110.
[3]Diez J. Arterial stiffness and extracellular matrix. Adv Cardiol 2007;44:76-95.
[4]Yasmin, McEniery CM, Wallace S, Dakham Z, Pulsalkar P, Maki-Petaja K, Ashby MJ, Cockcroft JR, Wilkinson IB.Matrix metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness. Arterioscler Thromb Vase Biol 2005;25:372-378.
[5]Wallace SM, Yasmin, McEniery CM, Maki-Petaja KM, Booth AD, Cockcroft JR, Wilkinson IB.Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction. Hypertension 2007;50:228-233.
[6]Fazio MJ, Mattei MG, Passage E, Chu ML, Black D, Solomon E, Davidson JM, Uitto J. Human elastin gene:new evidence for localization to the long arm of chromosome 7. Am J Hum Genet 1991;48:696-703.
[7]Rodriquez-Revenqa L, Badenas C, Carrio A, Mila M. Elastin mutation screening in a group of patients affected by vascular abnormalities. Pediatr Cardiol 2005;26:827-831.
[8]Kaushal R, Woo D, Pal P, Haverbusch M, Xi H, Moomaw C, Sekar P, Kissela B, Kleindorfer D, Flaherty M, Sauerbeck L, Chakraborty R, Broderick J, Deka R. Subarachnoid hemorrhage:tests of association with apolipoprotein E and elastin genes. BMC Med Genet 2007;8:49.
[9]Ewart AK, Morris C, Atkinson D, Jin W, Sternes K, Spallone P, Stock AD, Leppert M, Keating MT. Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat Genet 1993;5:11-16.
[10]Hanon O, Luong V, Mourad JJ, Bortolotto LA, Jeunemaitre X, Girerd X. Aging, carotid artery distensibility, and the Ser422Gly elastin gene polymorphism in humans. Hypertension 2001;38:1185-1189.
[11]Iwai N, Kajimoto K, Kokubo Y, Tomoike H. Extensive Genetic Analysis of 10 Candidate Genes for Hypertension in Japanese. Hypertension 2006;48:901-907.
[12]Akagawa H, Tajima A, Sakamoto Y, Krischek B, Yoneyama T, Kasuya H, Onda H, Hori T, Kubota M, Machida T, Saeki N, Hata A, Hashiguchi K, Kimura E, Kim CJ, Yang TK, Lee JY, Kimm K, Inoue I. A haplotype spanning two genes, ELN and LIMK1, decreases their transcripts and confers susceptibility to intracranial aneurysms. Human Molecular Genetics 2006; 15:1722-1734.
[13]Farnham JM, Camp NJ, Neuhausen SL, Tsuruda J, Parker D, MacDonald J, Cannon-Albright LA. Confirmation of chromosome 7qll locus for predisposition to intracranial aneurysm. Hum Genet 2004; 114:250-255.
[14]Onda H, Kasuya H, Yoneyama T, Takakura K, Hori T, Takeda J, Nakajima T, Inoue I. Genomewide-linkage and haplotype-association studies map intracranial aneurysm to chromosome 7q11. Am J Hum Genet 2001;69:804-819.
[15]Ruigrok YM, Seitz U, Wolterink S, Rinkel GJ, Wijmenga C, Urban Z. Association of polymorphisms and haplotypes in the elastin gene in Dutch patients with sporadic aneurysmal subarachnoid hemorrhage. Stroke 2004;35:2064-2068.
[16]Oliver JJ, Webb DJ. Noninvasive assessment of arterial stiffness and risk of atherosclerotic events. Arterioscler Thromb Vasc Biol 2003;23:554-566.
[17]Ni Y, Wang H, Hu D, Zhang W. The relationship between pulse wave velocity and pulse pressure in Chinese patients with essential hypertension. Hypertens Res 2003;26:871-874.
[18]Yasmin, McEniery CM, Wallace S, Mackenzie IS, Cockcroft JR, Wilkinson IB. C-reactive protein is associated with arterial stiffness in apparently healthy individuals. Arterioscler Thromb Vasc Biol 2004;24:969-974.
[19]Yamashina A, Tomiyama H, Takeda K, Tsuda H, Arai T, Hirose K, Koji Y, Hori S, Yamamoto Y. Validity, reproducibility, and clinical significance of noninvasive brachial-ankle pulse wave velocity measurement. Hypertens Res 2002;25:359-364.
[20]Xiao Z, Xiao J, Jiang Y, Zhang S, Yu M, Zhao J, Wei D, Cao H. A novel method based on ligase detection reaction for low abundant YIDD mutants detection in hepatitis B virus. Hepatol Res 2006;34:150-155.
[21]Faury G, Pezet M, Knutsen RH, Boyle WA, Heximer SP, McLean SE, Minkes RK, Blumer KJ, Kovacs A, Kelly DP, Li DY, Starcher B, Mecham RP. Developmental adaptation of the mouse cardiovascular system to elastin haploinsufficiency. J Clin Invest 2003;112:1419-1428.
[22]Eronen M, Peippo M, Hiippala A, Raatikka M, Arvio M, Johansson R, Kahkonen M. Cardiovascular manifestations in 75 patients with Williams syndrome. J Med Genet 2002;39:554-558.
[23]Kubo T, Miyata M, Minagoe S, Setoyama S, Maruyama I, Tei C. A simple oscillometric technique for determining new indices of arterial distensibility. Hypertens Res 2002;25:351-358.
[24]Brillante DG, O'Sullivan AJ, Howes LG. Arterial stiffness indices in healthy volunteers using non-invasive digital photoplethysmography.Blood Press 2008;17:116-123.
[25]London GM, Marchais SJ, Guerin AP, Pannier B. Arterial stiffness: pathophysiology and clinical impact. Clin Exp Hypertens 2004;26:689-699.
[1]Wallace SM, Yasmin, McEniery CM, Maki-Petaja KM, Booth AD, Cockcroft JR, et al. Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction. Hypertension 2007;50:228-233
[2]Safar ME., Levy BI., Struijker-Boudier H. Current perspectives on arterial stiffness and pulse pressure in hypertension and cardiovascular diseases. Circulation 2003; 107:2864-2869.
[3]Opdenakker G, Van den Steen PE, Dubois B, Nelissen I, Van Coillie E, Masure S, et al. Gelatinase B functions as regulator and effector in leukocyte biology. J Leukoc Biol 2001;69:851-859.
[4]Godin D, Ivan E, Johnson C, Magid R, Galis ZS. Remodeling of carotid artery is associated with increased expression of matrix metalloproteinases in mouse blood flow cessation model. Circulation 2000;102:2861-2866.
[5]Ye S, Eriksson P, Hamsten A, Kurkinen M, Humphries SE, Henney AM. Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem 1996; 271:13055-13060.
[6]Tan J, Hua Q, Xing X, Wen J, Liu R, Yang Z. Impact of the metalloproteinase-9/tissue inhibitor of metalloproteinase-1 system on large arterial stiffness in patients with essential hypertension. Hypertens Res 2007;30:959-963.
[7]Beevers G, Lip GY, O'Brien E. ABC of hypertension:The pathophysiology of hypertension. BMJ 2001,14;322:912-916.
[8]Yasmin, McEniery CM, O'Shaughnessy KM, Harnett P, Arshad A, Wallace S, et al. Variation in the human matrix metalloproteinase-9 gene is associated with arterial stiffness in healthy individuals. Arterioscler Thromb Vasc Biol 2006;26:1799-1805.
[9]Beilby JP, Chapman CM, Palmer LJ, McQuillan BM, Thompson PL, Hung J. Stromelysin-1 (MMP-3) gene 5A/6A promoter polymorphism is associated with blood pressure in a community population. J Hypertens 2005;23:537-542.
[10]Medley TL, Kingwell BA, Gatzka CD, Pillay P, Cole TJ. Matrix metalloproteinase-3 genotype contributes to age-related aortic stiffening through modulation of gene and protein expression. Circ Res 2003; 92:1254-1261.
[11]Higo S, Uematsu M, Yamagishi M, Ishibashi-Ueda H, Awata M, Morozumi T, et al. Elevation of plasma matrix metalloproteinase-9 in the culprit coronary artery in patients with acute myocardial infarction:clinical evidence from distal protection. Circ J 2005;69:1180-1185.
[12]Morgan AR, Zhang B, Tapper W, Collins A, Ye S. Haplotypic analysis of the MMP-9 gene in relation to coronary artery disease. J Mol Med 2003;81:321-326.
[13]Medley TL, Cole TJ, Dart AM, Gatzka CD, Kingwell BA. Matrix metalloproteinase-9 genotype luences large artery stiffness through effects on aortic gene and protein expression. Arterioscler Thromb Vasc Biol 2004; 24:1479-1484.
[14]Yasmin, McEniery CM, Wallace S, Dakham Z, Pulsalkar P, Maki-Petaja K, et al. Matrix metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness. Arterioscler Thromb Vasc Biol 2005; 25:372.
[15]Zhou S, Feely J, Spiers JP, Mahmud A. Matrix metalloproteinase-9 polymorphism contributes to blood pressure and arterial stiffness in essential hypertension. J Hum Hypertens 2007;21:861-867.
[16]Flamant M, Placier S, Dubroca C, Esposito B, Lopes I, Chatziantoniou C, et al. Role of matrix metalloproteinases in early hypertensive vascular remodeling. Hypertension 2007;50:212-218.
[17]17.Armstrong C, Abilleira S, Sitzer M, Markus HS, Bevan S. Polymorphisms in MMP family and TIMP genes and carotid artery intima-media thickness. Stroke 2007;38:2895-2899.
[18]Oliver JJ, Webb DJ. Noninvasive assessment of arterial stiffness and risk of atherosclerotic events. Arterioscler Thromb Vasc Biol 2003;23:554-566.
[19]Semba RD, Najjar SS, Sun K, Lakatta EG, Ferrucci L. Serum carboxymethyl-lysine, an advanced glycation end product, is associated with increased aortic pulse wave velocity in adults. Am J Hypertens 2009,2:74-79.
[20]McNulty M, Mahmud A, Feely J. Advanced glycation end-products and arterial stiffness in hypertension. Am J Hypertens 2007;20:242-247.
[21]Bots ML, Westerink J, Rabelink TJ, de Koning EJ. Assessment of flow-mediated vasodilatation (FMD) of the brachial artery:effects of technical aspects of the FMD measurement on the FMD response. Eur Heart J 2005;26:363-368.
[22]Martin C, Cameron J, McGrath B. Mechanical and circulating biomarkers in isolated clinic hypertension. Clin Exp Pharmacol Physiol 2008;35:402-408.
[23]Cockcroft JR. Exploring vascular benefits of endothelium-derived nitric oxide. Am J Hypertens.2005,18:177S-183S.
[24]Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. 2007 Guidelines for the Management of Arterial Hypertension:The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007;25:1105-1187.
[25]Xiao Z, Xiao J, Jiang Y, Zhang S, Yu M, Zhao J, et al. A novel method based on ligase detection reaction for low abundant YIDD mutants detection in hepatitis B virus. Hepatol Res 2006;34:150-155.
[26]Ye S. Influence of matrix metalloproteinase genotype on cardiovascular disease susceptibility and outcome. Cardiovasc Res 2006;69:636-645.
[27]Tsukahara S, Shinozaki M, Ikari K, Mochizuki T, Inoue E, Tomatsu T, et al. Effect of matrix metalloproteinase-3 functional SNP on serum matrix metalloproteinase-3 level and outcome measures in Japanese RA patients. Rheumatology (Oxford) 2008;7:41-44.
[28]Puddu P, Puddu GM, Zaca F, Muscari A. Endothelial dysfunction in hypertension. Acta Cardio 2000;55:221-232.
[29]Nichols WW, Epstein BJ. Actions of selected cardiovascular hormones on arterial stiffness and wave reflections. Curr Pharm Des 2009;15:304-320.
[30]Medley TL, Cole TJ, Dart AM, Gatzka CD, Kingwell BA. Matrix metalloproteinase-9 genotype luences large artery stiffness through effects on aortic gene and protein expression. Arterioscler Thromb Vase Biol 2004; 24:1479-1484.
[31]Jones GT, Phillips VL, Harris EL, Rossaak JI, van Rij AM. Functional matrix metalloproteinase-9 polymorphism (C-1562T) associated with abdominal aortic aneurysm. J Vase Surg 2003; 38:1363-1367.
[32]Rutter JL, Mitchell TI, Buttice G, Meyers J, Gusella JF, Ozelius LJ, et al. A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter creates an Ets binding site and augments transcription. Cancer Res 1998;58: 5321-5325.
[33]Zhang B, Dhillon S, Geary I, Howell WM, Iannotti F, Day IN, et al. Polymorphisms in matrix metalloproteinase-1,-3,-9, and-12 genes in relation to subarachnoid hemorrhage. Stroke 2001;32:2198-2202.
[2]Guidelines committee.2003 European society of hypertension-European society of cardiology guidelines for the management of arterial hypertension. J Hypertens,2003,21:1011-1053.
[3]Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. JAMA,2003,289:2560-2572.
[4]Franklin SS, Jacobs MJ, Wong ND, et al. Predominance of isolated systolic hypertension among middle-aged and elderly us hypertensives:analysis based on national health and nutrition examination survey(NHANES)III. Hypertension, 2001,37:869-874.
[5]Blacher J, Safar ME. Large-artery stiffness, hypertension and cardiovascular risk in older patients. Nature Clin Pract Cardiovasc Med,2005,2:450-455.
[6]Izzo JL Jr. Arterial stiffness and the systolic hypertension syndrome. Curr Opin Cardiol,2004,19:341-352.
[7]朱鼎良.我国高血压基因研究十年回顾和几点建议.中华心血管病杂志,2005，33：585-587.
[8]朱鼎良.开展高质量的高血压基因多态性关联研究.高血压杂志,2004,12：2-3.
[9]Doris PA, Fornage M. The transcribed genome and the heritable basis of essential hypertension. Cardiovasc Toxicol,2005,5:95-108.
[10]London GM, Marchais SJ, Guerin AP, et al. Arterial stiffness:pathophysiology and clinical impact. Clin Exp Hypertens,2004,26:689-699.
[11]Lakatta EG. Arterial and cardiac aging:major shareholders in cardiovascular disease enterprises. Part III:cellular and molecular cluesmto heart and arterial Aging. Ciculation,2003,107:490-497.
[12]Laurent S, Boutouyrie P, Lacolley P. Structural and genetic bases of arterial stiffness. Hypertension,2005,45:1050-1055.
[13]Hanon O, Luong V, Mourad JJ, et al. Aging, carotid artery distensibility, and the Ser422Gly elastin gene polymorphism in humans. Hypertension,2001,38: 1185-1189.
[14]Akagawa H, Tajima A, Sakamoto Y, et al. A haplotype spanning two genes, ELN and LIMK1, decreases their transcripts and confers susceptibility to intracranial aneurysms. Human Molecular Genetics,2006,15:1722-1734.
[15]Iwai N, Kajimoto K, Kokubo Y, et al. Extensive genetic analysis of 10 Candidate genes for hypertension in Japanese. Hypertension,2006,48: 901-907.
[16]Farnham JM, Camp NJ, Neuhausen SL, et al. Confirmation of chromosome 7q11 locus for predisposition to intracranial aneurysm. Hum Genet,2004,114: 250-255.
[17]Onda H, Kasuya H, Yoneyama T, et al. Genome wide-linkage and haplotype-association studies map intracranial aneurysm to chromosome 7qll. Am J Hum Genet,2001,69:804-819.
[18]Ruigrok YM, Seitz U, Wolterink S, et al.. Association of polymorphisms and haplotypes in the elastin gene in Dutch patients with sporadic aneurysmal subarachnoid hemorrhage. Stroke,2004,35:2064-2068.
[19]Deng L, Huang R, Xu DL, et al. A study on polymorphisms of elastin gene in Chinese Han patients with isolated systolic hypertension. Am J Hypertens,2009, 22:656-662.
[20]Opdenakker G, Van den Steen PE, Dubois B, et al. Gelatinase B functions as regulator and effector in leukocyte biology. J Leukoc Biol,2001,69:851-859.
[21]Godin D, Ivan E, Johnson C, et al. Remodeling of carotid artery is associated with increased expression of matrix metalloproteinases in mouse blood flow cessation model. Circulation,2000,102:2861-2866.
[22]Ye S, Eriksson P, Hamsten A, et al. Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem,1996,271:13055-13060.
[23]Tan J, Hua Q, Xing X, et al. Impact of the metalloproteinase-9/tissue inhibitor of metalloproteinase-1 system on large arterial stiffness in patients with essential hypertension. Hypertens Res,2007,30:959-963.
[24]Abilleira S, Bevan S, Markus HS. The role of genetic variants of matrix metalloproteinases in coronary and carotid atherosclerosis. J Med Genet,2006, 43:897-901.
[25]Blankenberg S, Rupprecht HJ, Poirier O, et al. Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation,2003,107:1579-1585.
[26]Yasmin, McEniery CM, O'Shaughnessy KM, et al. Variation in the human matrix metalloproteinase-9 gene is associated with arterial stiffness in healthy individuals. Arterioscler Thromb Vasc Biol,2006,26:1799-1805.
[27]Beilby JP, Chapman CM, Palmer LJ, et al. Stromelysin-1 (MMP-3) gene 5A/6A promoter polymorphism is associated with blood pressure in a community population. J Hypertens,2005,23:537-542.
[28]Beyzade S, Zhang S, Wong YK, et al. Influences of matrix metalloproteinase-3 gene variation on extent of coronary atherosclerosis and risk of myocardial infarction. J Am Coll Cardiol,2003,41:2130-2137.
[29]Medley TL., Kingwell BA., Gatzka CD., et al. Matrix metalloproteinase-3 genotype contributes to age-related aortic stiffening through modulation of gene and protein expression. Circ Res,2003,92:1254-1261.
[30]Higo S, Uematsu M, Yamagishi M, et al. Elevation of plasma matrix metalloproteinase-9 in the culprit coronary artery in patients with acute myocardial infarction:clinical evidence from distal protection. Circ J,2005,69: 1180-1185.
[31]Morgan AR, Zhang B, Tapper W, et al. Haplotypic analysis of the MMP-9 gene in relation to coronary artery disease. J Mol Med,2003,81:321-326.
[32]Yasmin, Sharon Wallace, Carmel M, et al. Matrix metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness. Arterioscler Thromb Vase Biol,2005,25:372-378.
[33]Lehoux S, Lemarie CA,Espostio B, et al. Pressure-induced matrix metalloprote-inase-9 contributes to early hypertensive remodeling. Circulation,2004,109: 1041-1047.
[34]Zhou S, Feely J, Spiers JP, et al. Matrix metalloproteinase-9 polymorphism contributes to blood pressure and arterial stiffness in essential hypertension. J Hum Hypertens,2007,21:861-867.
[35]Medley TL, Cole TJ, Dart AM, et al. Matrix metalloproteinase-9 genotype luences large artery stiffness through effects on aortic gene and protein expression. Arterioscler Thromb Vase Biol,2004,24:1479-1484.
[36]Armstrong C, Abilleira S, Sitzer M, et al. Polymorphisms in MMP family and TIMP genes and carotid artery intima-media thickness. Stroke,2007,38: 2895-2899.
[37]Oliver JJ, Webb DJ. Noninvasive assessment of arterial stiffness and risk of atherosclerotic events. Arterioscler Thromb Vasc Biol,2003,23:554-566.
[38]Semba RD, Najjar SS, Sun K, et al. Serum carboxymethyl-lysine, an advanced glycation end product, is associated with increased aortic pulse wave velocity in adults. Am J Hypertens,2009,2:74-79.
[39]McNulty M, Mahmud A, Feely J. Advanced glycation end-products and arterial stiffness in hypertension. Am J Hypertens,2007,20:242-247.
[40]Bots ML, Westerink J, Rabelink TJ, et al. Assessment of flow-mediated vasodilatation (FMD) of the brachial artery:effects of technical aspects of the FMD measurement on the FMD response. Eur Heart J,2005,26:363-368.
[41]Martin C, Cameron J, McGrath B. Mechanical and circulating biomarkers in isolated clinic hypertension. Clin Exp Pharmacol Physiol,2008,35:402-408.
[42]Cockcroft JR. Exploring vascular benefits of endothelium-derived nitric oxide. Am J Hypertens.,2005,18:177S-18.
[1]中国高血压防治指南起草委员会.2004年中国高血压防治指南(实用本).中华心血管病杂志,2004,32：1060-1064.
[2]Guidelines committee.2003 European society of hypertension-European society of cardiology guidelines for the management of arterial hypertension. J Hypertens,2003,21:1011-1053.
[3]Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. JAMA,2003,289:2560-2572.
[4]Franklin SS, Jacobs MJ, Wong ND, et al. Predominance of isolated systolic hypertension among middle-aged and elderly us hypertensives:analysis based on national health and nutrition examination survey(NHANES)III. Hypertension, 2001,37:869-874.
[5]Blacher J, Safar ME. Large-artery stiffness, hypertension and cardiovascular risk in older patients. Nature Clin Pract Cardiovasc Med,2005,2:450-455.
[6]Izzo JL Jr. Arterial stiffness and the systolic hypertension syndrome. Curr Opin Cardiol,2004,19:341-352.
[7]朱鼎良.我国高血压基因研究十年回顾和几点建议.中华心血管病杂志,2005,33(7)：585-587.
[8]朱鼎良.开展高质量的高血压基因多态性关联研究.高血压杂志,2004,122-3.
[9]Doris PA, Fornage M. The transcribed genome and the heritable basis of essential hypertension. Cardiovasc Toxicol,2005,5:95-108.
[10]London GM, Marchais SJ, Guerin AP, et al. Arterial stiffness:pathophysiology and clinical impact. Clin Exp Hypertens,2004,26:689-699.
[11]Lakatta EG. Arterial and cardiac aging:major shareholders in cardiovascular disease enterprises. Part III:cellular and molecular cluesmto heart and arterial Aging. Ciculation,2003,107:490-497.
[12]Laurent S, Boutouyrie P, Lacolley P. Structural and genetic bases of arterial stiffness. Hypertension,2005,45:1050-1055.
[13]Wallace SM, Yasmin, McEniery CM, et al. Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction. Hypertension,2007,50:228-233.
[14]Opdenakker G, Van den Steen PE, Dubois B, et al. Gelatinase B functions as regulator and effector in leukocyte biology. J Leukoc Biol,2001,69:851-859.
[15]Godin D, Ivan E, Johnson C, et al. Remodeling of carotid artery is associated with increased expression of matrix metalloproteinases in mouse blood flow cessation model. Circulation,2000,102:2861-2866.
[16]Ye S, Eriksson P, Hamsten A, et al. Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem,1996,271: 13055-13060.
[17]Tan J, Hua Q, Xing X, et al. Impact of the metalloproteinase-9/tissue inhibitor of metalloproteinase-1 system on large arterial stiffness in patients with essential hypertension. Hypertens Res,2007,30:959-963.
[18]Abilleira S, Bevan S, Markus HS. The role of genetic variants of matrix metalloproteinases in coronary and carotid atherosclerosis. J Med Genet,2006, 43:897-901.
[19]Blankenberg S, Rupprecht HJ, Poirier O, et al. Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation,2003,107:1579-1585.
[20]Yasmin, McEniery CM, O'Shaughnessy KM, et al. Variation in the human matrix metalloproteinase-9 gene is associated with arterial stiffness in healthy individuals. Arterioscler Thromb Vasc Biol,2006,26:1799-1805.
[21]Beilby JP, Chapman CM, Palmer LJ, et al. Stromelysin-1 (MMP-3) gene 5A/6A promoter polymorphism is associated with blood pressure in a community population. J Hypertens,2005,23:537-542.
[22]Beyzade S, Zhang S, Wong YK, et al. Influences of matrix metalloproteinase-3 gene variation on extent of coronary atherosclerosis and risk of myocardial infarction. J Am Coll Cardiol,2003,41:2130-2137.
[23]Medley TL, Kingwell BA, Gatzka CD, et al. Matrix metalloproteinase-3 genotype contributes to age-related aortic stiffening through modulation of gene and protein expression. Circ Res,2003,92:1254-1261.
[24]Higo S, Uematsu M, Yamagishi M, et al. Elevation of plasma matrix metalloproteinase-9 in the culprit coronary artery in patients with acute myocardial infarction:clinical evidence from distal protection. Circ J,2005,69: 1180-1185.
[25]Morgan AR, Zhang B, Tapper W, et al. Haplotypic analysis of the MMP-9 gene in relation to coronary artery disease. J Mol Med,2003,81:321-326.
[26]Yasmin, Sharon Wallace, Carmel M, et al. Matrix metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness. Arterioscler Thromb Vasc Biol,2005,25:372-378.
[27]Lehoux S, Lemarie CA, Espostio B, et al. Pressure-induced matrix metalloproteinase-9 contributes to early hypertensive remodeling. Circulation, 2004,109:1041-1047.
[28]Zhou S, Feely J, Spiers JP, et al. Matrix metalloproteinase-9 polymorphism contributes to blood pressure and arterial stiffness in essential hypertension. J Hum Hypertens,2007,21:861-867.
[29]Medley TL, Cole TJ, Dart AM, et al. Matrix metalloproteinase-9 genotype luences large artery stiffness through effects on aortic gene and protein expression. Arterioscler Thromb Vasc Biol,2004,24:1479-1484.
[30]Armstrong C, Abilleira S, Sitzer M, et al. Polymorphisms in MMP family and TIMP genes and carotid artery intima-media thickness. Stroke,2007,38: 2895-2899.
[31]Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure:the JNC 7 report. JAMA,2003,289:2560-2572.
[32]European Society of Hypertension-European Society of Cardiology Guidelines Committee.2003 European Society of Hypertension-Eu isolated systolic hypertension among middle-aged and elderly US hypertensives:analysis based on National Health and Nutrition Examination Survey (NHANES) III. Hypertension,2001,37:869-874.
[33]Primatesta P, Poulter NR. Hypertension management and control among English adults aged 65 years and older in 2000 and 2001. J Hypertens,2004,22: 1093-1098.
[34]Safar ME. Hypothesis on isolated systolic hypertension in the elderly. J Hum Hypertens,1999,13:813-815.
[35]Sethi AA, Nordestgaard BG, Agerholm-Larsen B, et al. Angiotensinogen polymorphisms and elevated blood pressure in the general population:the Copenhagen City Heart Study. Hypertension,2001,37:875-881.
[36]Jackson ZS, Gotlieb A I, Langille BL. Wall tissue remodeling regulates longitudinal tension in arteries. Circ Res,2002,90:918-925.
[37]Wang MY, Lakatta EG. Altered regulation of matrix metalloproteinase 2 in aortic remodeling during aging. Hypertension,2002,39:865-874.
[38]Wang M, Zhang J, Sp inetti G, et al. Angiotensin II activates matrix metallop-roteninase type II and mimics age-associated carotid arterial remodeling in young rats. Am J Pathol,2005,167:1429-1442.
[39]Rodriguez-Vita J, Ruiz Ortega M, Ruperez M, et al. Endothelin-1, via ETA receptor and independently of transforming growth factor beta, increases the connective tissue growth factor in vascular smooth muscle cells. Circ Res,2005, 97:125-134.
[40]Shofuda T, Shofuda K, FerriN, et al. Cleavage of focal adhesion kinase in vascular smooth muscle cells overexp ressingmembrane type matrixmetallop roteinases. Arterioscler Thromb Vasc B iol,2004,24:839-844.
[41]Filippov S, Koenig GC, Chun TH, et al. MMP2 matrix metalloproteinase directs arterialwall invasion and neointima formation by vascular smooth muscle cells. J Exp Med,2005,202:663-671.
[42]McEniery CM, Wallace S, Dakham Z, et al,Matrix metalloproteinas-9 (MMP-9),MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness. A rterioscler Thromb Vasc B iol,2005,25: 372-378.
[43]Medley TL, Kingwell BA, Gatzka CD, et al. Matrix metalloproteinase-3 genotype contributes to age-related aortic stiffening through modulation of gene and protein expression. Circ Res,2003,92:1254-1261.
[44]Ergul A, Portik Dobos V, Hutchinson J, et al. Downregulation of vascular matrix metalloproteinase inducer and activator proteins in hypertensive patients. Am J Hypertens,2004,17:775-782.
[45]Bouvet C, Gilbert LA, Girardot D, et al. Different involvement of extracellular matrix components in small and large arteries during chronic NO synthase inhibition. Hypertension,2005,45:432-437.
[46]Lepetit H, Eddahibi S, Fadel E, et al. Smoothmuscle cell matrix metallop-roteinnase in idiopathic pulmonary aterial hypertension. Eur Resp ir J,2005, 25:834-842.
[47]Defawe OD, Kenagy RD, Choi C, et al. MMP-9 regulates both positively andnegatively collagen gel contraction:a nonp roteolytic function of MMP-9.Cardiovasc Res,2005,66:402-409.
[48]Yasmin A, McEniery CM, Wallace S, et al. Matrix metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hyretension and arterial stiffness. Arterioscler Thromb Vasc Biol,2005,25 372-378.
[49]Dhingra R, Pencina MJ, Schrader P, et all. Relations of matrix remodeling biomarkers to blood pressure progression and incidence of hypertension in the community. Circulation,2009,119:1101-1107.
[50]Misra S, Fu AA, Puggioni A, et al. Increased shear stress with up regulation of VEGF-A and its recep tors and MMP-2, MMP-9, and TIMP-1 in venous stenosis of hemodialysis grafts. Am J Physiol Heart Circ Physiol,2008,294 H2219-2230.
[51]Walter ERA, Neetu T, Utpal S, et al. Inhibition of matrix metalloproteinase-9 reverses changes in vascular wall structure and function of thoracic aorta of Dah.salt-sensitive rats. FASEB J,2009,23:1017-1032.
[52]L i H, Simom H, Bocan TM, et al. MMP/TIMP expression in spontaneously hypertensive heart failure rats:the effect of ACEI and MMP-inhibition 1.Cardiovasc Res,2000,46:298-306.
[53]Derosa G, Angelo A, Ciccarelli L, et al. Matrix metallop roteinase-2,-9, and tissue inhibitor of metallop roteinase-1 in patientswith hypertension. Endothelium,2006,13:227-231.
[54]Heymans S, Schroen B,Vermeersch P, et al. Increased cardiac expression of tissue inhibitor of metallop roteinase-1 and tissue inhibitor of metallop roteinase-2 is related to cardiac fibrosis and dysfunction in the chronic pressure-overloaded human heart. Circulation,2005,112:1136-1144.
[55]Sakata Y, Yamamoto K, Mano T, et al. Activation of matrix metalloproteinases precedes left ventricular remodeling in hypertensive heart failure rats:its inhibitiion as a primary effect of angiotensin-conerting enzyme inhibitor. Circulation,2004,109:2143-2149.
[56]Saglam M, Karakaya O, Esen AM, et al. Contribution of plasma matrix metallop roteinases to development of left ventricular hypertrophy and diastolic dysfunction in hypertensive subjects. Tohoku J Exp Med,2006,208:117-122.
[57]Reinhardt D, Sigusch HH, Hensse J, et al. Cardiac remodelling in end stage heart failure:up regulation of matrix metalloproteinase (MMP) irrespective of the underlying disease, and evidence for a direct inhibitory effect of ACE inhititors on MMP. Heart,2002,88:525-530.
[58]Williams RN, Parsons SL, Morris TM, et al. Inhibition of matrix metallop-roteinase activity and growth of gastric adenocarcinoma cells by an angiotensin conerting enzyme inhibitor in vitro and murine models. Eur J Surg Oncol, 2005,31:1042-1050.
[59]Bautista LE, Lopez, Jaramillo P, et al. Is C-reative protein an independent risk factor for essential hypertension. J Hypertens,2001,19:857-861.
[60]Bautista LE, Vera LM, Arenas IA, et al. Independent association between inflammatory markers (C-reactive protein, interleukin-6, and TNF-alpha) and essential hypertension. J Hum Hypertens,2005,19:149-154.
[61]Sesso HD, Buring JE, Rifai N, et al. C-reactive protein and the risk of developing hypertension. JAMA,2003,290:2945-2951.
[62]Das UN. Metabolic syndrome X:an inflammatory condition?. Curr Hypertens Rep,2004,6:66-73.
[63]Solini A, Santini E, Passaro A, et al. Family history of hypertension, anthropometric parameters and markers of early atherosclerosis in young healthy individuals. J Hum Hypertens,2009,2:151-157.
[64]Palei AC, Sandrim VC, Cavalli RC, et al. Comparative assessment of matrix metalloproteinase (MMP)-2 and MMP-9, and their inhibitors, tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 in preeclamp sia and gestational hyertension. Clin Biochem,2008,41:875-880.
[65]Djuric T, Zivkovic M, Radak D, et al. Association of MMP-35A/6A gene polymorphism with susceptibility to carotid atherosclerosis. Clin Biochem,2008, 41:1326-1329.
[66]康照梅,牟善初,张晓英,等MMP-2、MMP-3、TIMP-1及氯沙坦与氨氯地平在老年前期自发性高血压大鼠肾硬化中的作用及其机理探讨.中华老年多器官疾病杂志,2003,2：211-215.
[1]Najjar SS, Scuteri A, Lakatta EG. A rterial aging. Is it an immutable cardiovascular risk factor?. Hypertension,2005,46:454-462.
[2]Safar ME. Systolic blood pressure, pulse pressure and arterial stiffness as cardiovascular risk factors. Curr Op in Nephrol Hypertens,2001,10:257-261.
[3]Laurent S, Boutouyrie P, Lacolley P. Structural and genetic bases of arterial stiffness.Hypertension,2005,45:1050-1055.
[4]Izzo JL Jr. Arterial stiffness and the systolic hypertension syndrome. Curr Opin Cardiol,2004,19:341-352.
[5]Yambe M, Tomiyama H, Yamada J, et al. Arterial stiffness and progression to hypertension in Japanese male subjects with high normal blood pressure. J Hypertens,2007,25:87-93.
[6]Beltran A, McVeigh G, Morgan D, et al. Arterial compliance abnormalities in isolated systolic hypertension. Am J Hypertens,2001,14:1007-1011.
[7]Wallace SM, Yasmin, McEniery CM, et al. Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction. Hypertension,2007,50:228-233.
[8]Newsholme P, Homem De, Bittencourt PI, et al. Exercise and possible molecular mechanisms of protection from vascular disease and diabetes:the central role of ROS and nitric oxide. Clin Sci,.2009,118:341-349.
[9]Beevers G, Lip GY, O'Brien E. ABC of hypertension:The pathophysiology of hypertension. BMJ,2001,14:912-916.
[10]Oliver JJ, Webb DJ. Noninvasive assessment of arterial stiffness and risk of atherosclerotic events. Arterioscler Thromb Vasc Biol,2003,23:554-566.
[11]Semba RD, Najjar SS, Sun K, et al. Serum carboxymethyl-lysine, an advanced glycation end product, is associated with increased aortic pulse wave velocity in adults. Am J Hypertens,2009,2:74-79.
[12]McNulty M, Mahmud A, Feely J. Advanced glycation end-products and arterial stiffness in hypertension. Am J Hypertens,2007,20:242-247.
[13]Bots ML, Westerink J, Rabelink TJ, et al. Assessment of flow-mediated vasodilatation (FMD) of the brachial artery:effects of technical aspects of the FMD measurement on the FMD response. Eur Heart J,2005,26:363-368.
[14]Martin C, Cameron J, McGrath B. Mechanical and circulating biomarkers in isolated clinic hypertension. Clin Exp Pharmacol Physiol,2008,35:402-408.
[15]Cockcroft JR. Exploring vascular benefits of endothelium-derived nitric oxide. Am J Hypertens,.2005,18:177S-183S.
[16]Cohn JN. Vascular wall function as a risk marker for cardiovascular disease. J Hypertens,1999,17:41-44.
[17]Giovanni de Simone, et al.Stroke volume/pulse pressure ratio and cardiovascular risk in artrial hypertension. Hypertension,1999,33:800-805.
[18]任军梅,王瑞英.老年高血压患者脉压与靶器官损害.心血管病学进展,2005,26：141-143.
[19]丁跃有,张维忠.高血压动脉弹性功能无创性评价.高血压杂志,2002,10：503-504.
[20]Goldwyn RM. Arterial pressure pulse contour analysis via a mechanical model for the clinical quanification of human vascular properties. IEEE Trans Biomed, 1967，14：11-17.
[21]丁跃有,张维忠.健康人与高血压患者动脉弹性功能比较.高血压杂志,2003,11：333-336.
[22]刘丽芳,谢晋湘.汉族人群中血压与动脉硬化关系的研究.中国循环杂志,2003,18：129-131.
[23]王炳和,相敬林.一种无创性测定桡动脉脉搏波速度的方法及影响脉搏波速度的因素.生物医学工程学杂志,2000,17：179-182.
[24]Asmar R, Topouchian J, et al. Assessment of arterial distensibility by antomatic pulse wave velocity measurement. Validation and clinical application studies. Hypertens,1995,26:485-490.
[25]Tomoki Shokawa, Minchinori Imazu, et al. Pulse wave velocity predicts cardiovascular mortality findings from the Hawaii-Los Angeles-Hiroshima Study. Circ J,2005,69:259-264.
[26]Naidu MU, Reddy BM, Yashmaina S, et al. Validity and reproducibility of arterial pulse wave velocity measummem using new device with oscillometric technique:a pilot study. Biomed Eng Online,2005,4:49.
[27]胡大一,马长生主编.心脏病学实践2007-新进展与临床案例.北京：人民卫生出版社,2007,10：311-319.
[28]Jadhav UM, Kadam NN. Non-invasive assessmem of arterial stiffness by pulse wave velocity correlates with endothelial dysfunction. Indian Heart J,2005,57: 226-232.
[29]Kochkina MS, Zateishchikov DA, Sidorenko BA. Measurement of arterial stiffness and its clinical value. Kardiologiia,2005,45:63-71.
[30]张志勉,胡利芳,梁济乐,等.老年高血压合并动脉粥样硬化患者主动脉僵硬度的临床研究.山东大学学报(医学版),2005,43：57-59.
[31]华琦,谭静,刘东霞,等.高血压病患者颈-股动脉和颈-桡动脉脉搏波速度改变及其影响因素.中华心血管病杂志,2005,33：1088-1091.
[32]谭静,华琦,邢绣荣,等.高血压病患者脉搏波速度与动态脉压的相关性研 究.首都医科大学学报,2007,28：101-103.
[33]Benetos A, Adamopoulos C, Bureau JM, et al. Determinants of accelerated progression of arterial stiffness in normotensive subjects and in treated hypertensive subjects over a year period. Circulation,2002,105:1202-1207.
[34]Protogerou A, Blacher J, Stergiou GS, et al. Blood pressure response under chronic antihypertensive drug therapy:the role of aortic stiffness in the REASON (Preterax in Regression of Arterial Stiffness in a Controlled Double-Blind)study. J Am Coil Cardiol,2009,53:445-451.
[35]张丽,黄晶,李祥嫒,等.高血压治疗前后PWV的相关性研究.重庆医科大学学报,2008,33：207-209.
[36]Soro-Paavonen A, Watson AM, Li J, et al. Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes. Diabetes.,2008,57:2461-2469.
[37]Yan SF, Ramasamy RH, Naka YF Glycation, et al. A scaffold for the macrovascular complications of diabetes and beyond. Circ Res,2003,93: 1159-1169.
[38]郭志坚,侯凡凡,张训,等.晚期糖基化终产物通过p38信号通路抑制内皮细胞合成一氧化氮的研究.中华医学杂志,2002,19：1328-1331.
[39]Wallace SM, Yasmin, McEniery CM, et al. Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction. Hypertension,2007,50:228-233.
[1]Zieman S J, Kass D A. Advanced glycation end products cross-linking in the cardiovascular system potential therapeutic target for cardiovascular disease. Drugs,2004,64:2459-2470.
[2]许顶立,刘艳玲,孟素荣,等.冠心病患者血清晚期糖基化终产物Nε-羧甲 基赖氨酸含量的变化.中华老年心脑血管病杂志,2000,2：161-163.
[3]Semba RD, Najjar SS, Sun K, et al. Serum carboxymethyl-lysine, an advanced glycation end product, is associated with increased aortic pulse wave velocity in adults. Am J Hypertens,2009,2:74-79.
[4]McNulty M, Mahmud A, Feely J. Advanced glycation end-products and arterial stiffness in hypertension. Am J Hypertens,2007,20:242-247.
[5]Wallace SM, Yasmin, McEniery CM, et al. Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction. Hypertension,2007,50:228-233.
[6]庞战军.Griess试剂法-自由基医学研究方法[M],北京,人民卫生出版社,224-226.
[7]Soro-Paavonen A, Watson AM, Li J, et al. Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes. Diabetes.,2008,57:2461-2469.
[8]Jandeleit-Dahm K, Cooper ME. The role of AGEs in cardiovascular disease. Curr Pharm Des,.2008,14:979-986.
[9]吴雅利,雷梦觉,刘秋玲,等.单纯收缩期高血压年龄与血管内皮功能对大动脉僵硬度的影响.中华高血压杂志,2008,16：704-706.
[10]Yan SF, Ramasamy RH, Naka YF Glycation, et al. A scaffold for the macrovascular complications of diabetes and beyond. Circ Res,2003,93: 1159-1169.
[11]郭志坚,侯凡凡,张训,等.晚期糖基化终产物通过p38信号通路抑制内皮细胞合成一氧化氮的研究.中华医学杂志,2002,19：1328-1331.
[1]Wachtell K,Okin PM,Olsen MH,et al.Regression of electrocardiographic left ventricular hypertrophy during antihypertensive therapy and reduction in sudden cardiac death:the LIFE Study. Circulation,2007,116:700-705.
[2]黄丽娟,谢良地,陈翠林,等.原发性高血压左室肥厚患者的血管内皮依赖性舒张功能.中华高血压杂志,2009,17：737-742.
[3]贺利平,赵兴胜,吴云.高血压左室肥厚与三种血管活性因子水平的相关性研究.中国心血管病研究,2008,6：346-348.
[4]宋涛,葛志明,巩会萍,等.原发性高血压左室肥厚患者动脉结构和功能改变的临床研究.中国超声医学杂志,2008,24：123-126.
[5]Devereux RB,Alonso DR,Lutas EM,et al. Echocardiographic assessment of left ventricular hypertrophy:comparison to necropsy findings. Am J Cardiol 1986,57:450-458.
[6]Wallace SM,Yasmin,McEniery CM,et al. Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction. Hypertension,2007,50:228-233.
[7]Bots ML,Westerink J,Rabelink TJ,et al. Assessment of flow-mediated vasodilatation (FMD) of the brachial artery:effects of technical aspects of the FMD measurement on the FMD response. Eur Heart J,2005,26:363-368.
[8]Xu JZ,Zhang Y,Wu SN,et al.Impaired endothelial function in hypertensive patients with target organ damage. J Hum Hypertens,2009,23:751-757.
[9]陈明,胡申江,张健,等.不同危险度的高血压病人血管内皮功能.高血压杂志,2006,14：257-260.
[10]Pechanova O,Kunes J,Dobesova Z,et al. N-acetylcysteine-induced increase of NO synthase activity in the brain of normotensive and hypertensive rats. J Physiol Pharmacol,2009,60:21-25.
[11]Lind L.Left ventricular mass is related to endothelium-dependent vasodilation in the forearm, but not in the brachial artery, in elderly subjects:the Prospective Investigation of the Vasculature in Uppsala Seniors study. J Hum Hypertens,2008,22:767-773.
[12]Aubin MC, Carrier M, Shi YF,et al. Role of probucol on endothelial dysfunction of epicardial coronary arteries associated with left ventricular hypertrophy. J Cardiovasc Pharmacol,2006,47:702-710.
[13]McNulty M,Mahmud A,Feely J. Advanced glycation end-products and arterial stiffness in hypertension. Am J Hypertens,2007,20:242-247.
[14]郭志坚,侯凡凡,张训,等.晚期糖基化终产物通过p38信号通路抑制内皮细胞合成一氧化氮的研究.中华医学杂志,2002,19：1328-1331.
[15]Yan SF,Ramasamy R,Schmidt AM,et al.Receptor for AGE (RAGE) and its ligands-cast into leading roles in diabetes and the inflammatory response. J Mol Med,2009,87:235-247.
[1]Deng L, Huang R, Chen Z, et al. A study on polymorphisms of elastin gene in Chinese Han patients with isolated systolic hypertension. Am J Hyperten,2009, 22:656-662.
[2]Xiao Z, Xiao J, Jiang Y, et al. A novel method based on ligase detection reaction for low abundant YIDD mutants detection in hepatitis B virus. Hepatol Res, 2006,34:150-155.
[3]Wallace SM, Yasmin, McEniery CM, et al. Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction. Hypertension,2007,50:228-233.
[4]文灿,朱星红.动脉弹性蛋白的研究进展.中国病理生理杂志,2001,17：1029-1033.
[5]Tsoporis J, Keeley FW, Lee RMKW, et al. Arterial vasodilation and vascular connective tissue changes in spontaneously hypertensive rats. J Cardiovas Pharmac,1998,31:960-962.
[6]Godin D, Ivan E, Johnson C, et al. Remodeling of carotid artery is associated with increased expression of matrix metalloproteinases in mouse blood flow cessation model. Circulation,2000,102:2861-2866.
[7]Ye S, Eriksson P, Hamsten A, et al. Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem,1996,271:13055-13060.
[8]Hanon O, Luong V, Mourad JJ, et al. Aging, carotid artery distensibility, and the Ser422Gly elastin gene polymorphism in humans. Hypertension,2001,38: 1185-1189.
[9]Akagawa H, Tajima A, Sakamoto Y, et al. A haplotype spanning two genes, ELN and LIMK1, decreases their transcripts and confers susceptibility to intracranial aneurysms. Human Molecular Genetics,2006,15:1722-1734.
[10]Iwai N, Kajimoto K, Kokubo Y, et al. Extensive Genetic analysis of 10 Candidate genes for hypertension in Japanese. Hypertension,2006,48: 901-907.
[11]Medley TL, Kingwell BA, Gatzka CD, et al. Matrix metalloproteinase-3 genotype contributes to age-related aortic stiffening through modulation of gene and protein expression. Circ Res,2003,92:1254-1261.
[12]Beyzade S, Zhang S, Wong YK, et al. Influences of matrix metalloproteinase-3 gene variation on extent of coronary atherosclerosis and risk of myocardial infarction. J Am Coll Cardiol,2003,41:2130-2137.
[13]Beilby JP, Chapman CM, Palmer LJ, et al. Stromelysin-1 (MMP-3) gene 5A/6A promoter polymorphism is associated with blood pressure in a community population. J Hypertens,2005,23:537-542.
[14]Higo S, Uematsu M, Yamagishi M, et al. Elevation of plasma matrix metalloproteinase-9 in the culprit coronary artery in patients with acute myocardial infarction:clinical evidence from distal protection. Circ J,2005,69: 1180-1185.
[15]Morgan AR, Zhang B, Tapper W, et al. Haplotypic analysis of the MMP-9 gene in relation to coronary artery disease. J Mol Med,2003,81:321-326.
[16]Medley TL, Cole TJ, Dart AM, et al. Matrix metalloproteinase-9 genotype luences large artery stiffness through effects on aortic gene and protein expression. Arterioscler Thromb Vasc Biol,2004,24:1479-1484.
[17]Yasmin, McEniery CM, Wallace S, et al. Matrix metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness. Arterioscler Thromb Vasc Biol,2005,25:372.
[1]Essalihi R, Dao HH, Yamaguchi N, Moreau P.A new model of isolated systolic hypertension induced by chronic warfarin and vitamin K1 treatment. Am J Hypertens 2003;16:103-110.
[2]Essalihi R, Dao HH, Yamaguchi N, Moreau P. A new model of isolated systolic hypertension induced by chronic warfarin and vitamin K1 treatment. Am J Hypertens 2003;16:103-110.
[3]Diez J. Arterial stiffness and extracellular matrix. Adv Cardiol 2007;44:76-95.
[4]Yasmin, McEniery CM, Wallace S, Dakham Z, Pulsalkar P, Maki-Petaja K, Ashby MJ, Cockcroft JR, Wilkinson IB.Matrix metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness. Arterioscler Thromb Vase Biol 2005;25:372-378.
[5]Wallace SM, Yasmin, McEniery CM, Maki-Petaja KM, Booth AD, Cockcroft JR, Wilkinson IB.Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction. Hypertension 2007;50:228-233.
[6]Fazio MJ, Mattei MG, Passage E, Chu ML, Black D, Solomon E, Davidson JM, Uitto J. Human elastin gene:new evidence for localization to the long arm of chromosome 7. Am J Hum Genet 1991;48:696-703.
[7]Rodriquez-Revenqa L, Badenas C, Carrio A, Mila M. Elastin mutation screening in a group of patients affected by vascular abnormalities. Pediatr Cardiol 2005;26:827-831.
[8]Kaushal R, Woo D, Pal P, Haverbusch M, Xi H, Moomaw C, Sekar P, Kissela B, Kleindorfer D, Flaherty M, Sauerbeck L, Chakraborty R, Broderick J, Deka R. Subarachnoid hemorrhage:tests of association with apolipoprotein E and elastin genes. BMC Med Genet 2007;8:49.
[9]Ewart AK, Morris C, Atkinson D, Jin W, Sternes K, Spallone P, Stock AD, Leppert M, Keating MT. Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat Genet 1993;5:11-16.
[10]Hanon O, Luong V, Mourad JJ, Bortolotto LA, Jeunemaitre X, Girerd X. Aging, carotid artery distensibility, and the Ser422Gly elastin gene polymorphism in humans. Hypertension 2001;38:1185-1189.
[11]Iwai N, Kajimoto K, Kokubo Y, Tomoike H. Extensive Genetic Analysis of 10 Candidate Genes for Hypertension in Japanese. Hypertension 2006;48:901-907.
[12]Akagawa H, Tajima A, Sakamoto Y, Krischek B, Yoneyama T, Kasuya H, Onda H, Hori T, Kubota M, Machida T, Saeki N, Hata A, Hashiguchi K, Kimura E, Kim CJ, Yang TK, Lee JY, Kimm K, Inoue I. A haplotype spanning two genes, ELN and LIMK1, decreases their transcripts and confers susceptibility to intracranial aneurysms. Human Molecular Genetics 2006; 15:1722-1734.
[13]Farnham JM, Camp NJ, Neuhausen SL, Tsuruda J, Parker D, MacDonald J, Cannon-Albright LA. Confirmation of chromosome 7qll locus for predisposition to intracranial aneurysm. Hum Genet 2004; 114:250-255.
[14]Onda H, Kasuya H, Yoneyama T, Takakura K, Hori T, Takeda J, Nakajima T, Inoue I. Genomewide-linkage and haplotype-association studies map intracranial aneurysm to chromosome 7q11. Am J Hum Genet 2001;69:804-819.
[15]Ruigrok YM, Seitz U, Wolterink S, Rinkel GJ, Wijmenga C, Urban Z. Association of polymorphisms and haplotypes in the elastin gene in Dutch patients with sporadic aneurysmal subarachnoid hemorrhage. Stroke 2004;35:2064-2068.
[16]Oliver JJ, Webb DJ. Noninvasive assessment of arterial stiffness and risk of atherosclerotic events. Arterioscler Thromb Vasc Biol 2003;23:554-566.
[17]Ni Y, Wang H, Hu D, Zhang W. The relationship between pulse wave velocity and pulse pressure in Chinese patients with essential hypertension. Hypertens Res 2003;26:871-874.
[18]Yasmin, McEniery CM, Wallace S, Mackenzie IS, Cockcroft JR, Wilkinson IB. C-reactive protein is associated with arterial stiffness in apparently healthy individuals. Arterioscler Thromb Vasc Biol 2004;24:969-974.
[19]Yamashina A, Tomiyama H, Takeda K, Tsuda H, Arai T, Hirose K, Koji Y, Hori S, Yamamoto Y. Validity, reproducibility, and clinical significance of noninvasive brachial-ankle pulse wave velocity measurement. Hypertens Res 2002;25:359-364.
[20]Xiao Z, Xiao J, Jiang Y, Zhang S, Yu M, Zhao J, Wei D, Cao H. A novel method based on ligase detection reaction for low abundant YIDD mutants detection in hepatitis B virus. Hepatol Res 2006;34:150-155.
[21]Faury G, Pezet M, Knutsen RH, Boyle WA, Heximer SP, McLean SE, Minkes RK, Blumer KJ, Kovacs A, Kelly DP, Li DY, Starcher B, Mecham RP. Developmental adaptation of the mouse cardiovascular system to elastin haploinsufficiency. J Clin Invest 2003;112:1419-1428.
[22]Eronen M, Peippo M, Hiippala A, Raatikka M, Arvio M, Johansson R, Kahkonen M. Cardiovascular manifestations in 75 patients with Williams syndrome. J Med Genet 2002;39:554-558.
[23]Kubo T, Miyata M, Minagoe S, Setoyama S, Maruyama I, Tei C. A simple oscillometric technique for determining new indices of arterial distensibility. Hypertens Res 2002;25:351-358.
[24]Brillante DG, O'Sullivan AJ, Howes LG. Arterial stiffness indices in healthy volunteers using non-invasive digital photoplethysmography.Blood Press 2008;17:116-123.
[25]London GM, Marchais SJ, Guerin AP, Pannier B. Arterial stiffness: pathophysiology and clinical impact. Clin Exp Hypertens 2004;26:689-699.
[1]Wallace SM, Yasmin, McEniery CM, Maki-Petaja KM, Booth AD, Cockcroft JR, et al. Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction. Hypertension 2007;50:228-233
[2]Safar ME., Levy BI., Struijker-Boudier H. Current perspectives on arterial stiffness and pulse pressure in hypertension and cardiovascular diseases. Circulation 2003; 107:2864-2869.
[3]Opdenakker G, Van den Steen PE, Dubois B, Nelissen I, Van Coillie E, Masure S, et al. Gelatinase B functions as regulator and effector in leukocyte biology. J Leukoc Biol 2001;69:851-859.
[4]Godin D, Ivan E, Johnson C, Magid R, Galis ZS. Remodeling of carotid artery is associated with increased expression of matrix metalloproteinases in mouse blood flow cessation model. Circulation 2000;102:2861-2866.
[5]Ye S, Eriksson P, Hamsten A, Kurkinen M, Humphries SE, Henney AM. Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem 1996; 271:13055-13060.
[6]Tan J, Hua Q, Xing X, Wen J, Liu R, Yang Z. Impact of the metalloproteinase-9/tissue inhibitor of metalloproteinase-1 system on large arterial stiffness in patients with essential hypertension. Hypertens Res 2007;30:959-963.
[7]Beevers G, Lip GY, O'Brien E. ABC of hypertension:The pathophysiology of hypertension. BMJ 2001,14;322:912-916.
[8]Yasmin, McEniery CM, O'Shaughnessy KM, Harnett P, Arshad A, Wallace S, et al. Variation in the human matrix metalloproteinase-9 gene is associated with arterial stiffness in healthy individuals. Arterioscler Thromb Vasc Biol 2006;26:1799-1805.
[9]Beilby JP, Chapman CM, Palmer LJ, McQuillan BM, Thompson PL, Hung J. Stromelysin-1 (MMP-3) gene 5A/6A promoter polymorphism is associated with blood pressure in a community population. J Hypertens 2005;23:537-542.
[10]Medley TL, Kingwell BA, Gatzka CD, Pillay P, Cole TJ. Matrix metalloproteinase-3 genotype contributes to age-related aortic stiffening through modulation of gene and protein expression. Circ Res 2003; 92:1254-1261.
[11]Higo S, Uematsu M, Yamagishi M, Ishibashi-Ueda H, Awata M, Morozumi T, et al. Elevation of plasma matrix metalloproteinase-9 in the culprit coronary artery in patients with acute myocardial infarction:clinical evidence from distal protection. Circ J 2005;69:1180-1185.
[12]Morgan AR, Zhang B, Tapper W, Collins A, Ye S. Haplotypic analysis of the MMP-9 gene in relation to coronary artery disease. J Mol Med 2003;81:321-326.
[13]Medley TL, Cole TJ, Dart AM, Gatzka CD, Kingwell BA. Matrix metalloproteinase-9 genotype luences large artery stiffness through effects on aortic gene and protein expression. Arterioscler Thromb Vasc Biol 2004; 24:1479-1484.
[14]Yasmin, McEniery CM, Wallace S, Dakham Z, Pulsalkar P, Maki-Petaja K, et al. Matrix metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness. Arterioscler Thromb Vasc Biol 2005; 25:372.
[15]Zhou S, Feely J, Spiers JP, Mahmud A. Matrix metalloproteinase-9 polymorphism contributes to blood pressure and arterial stiffness in essential hypertension. J Hum Hypertens 2007;21:861-867.
[16]Flamant M, Placier S, Dubroca C, Esposito B, Lopes I, Chatziantoniou C, et al. Role of matrix metalloproteinases in early hypertensive vascular remodeling. Hypertension 2007;50:212-218.
[17]17.Armstrong C, Abilleira S, Sitzer M, Markus HS, Bevan S. Polymorphisms in MMP family and TIMP genes and carotid artery intima-media thickness. Stroke 2007;38:2895-2899.
[18]Oliver JJ, Webb DJ. Noninvasive assessment of arterial stiffness and risk of atherosclerotic events. Arterioscler Thromb Vasc Biol 2003;23:554-566.
[19]Semba RD, Najjar SS, Sun K, Lakatta EG, Ferrucci L. Serum carboxymethyl-lysine, an advanced glycation end product, is associated with increased aortic pulse wave velocity in adults. Am J Hypertens 2009,2:74-79.
[20]McNulty M, Mahmud A, Feely J. Advanced glycation end-products and arterial stiffness in hypertension. Am J Hypertens 2007;20:242-247.
[21]Bots ML, Westerink J, Rabelink TJ, de Koning EJ. Assessment of flow-mediated vasodilatation (FMD) of the brachial artery:effects of technical aspects of the FMD measurement on the FMD response. Eur Heart J 2005;26:363-368.
[22]Martin C, Cameron J, McGrath B. Mechanical and circulating biomarkers in isolated clinic hypertension. Clin Exp Pharmacol Physiol 2008;35:402-408.
[23]Cockcroft JR. Exploring vascular benefits of endothelium-derived nitric oxide. Am J Hypertens.2005,18:177S-183S.
[24]Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. 2007 Guidelines for the Management of Arterial Hypertension:The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007;25:1105-1187.
[25]Xiao Z, Xiao J, Jiang Y, Zhang S, Yu M, Zhao J, et al. A novel method based on ligase detection reaction for low abundant YIDD mutants detection in hepatitis B virus. Hepatol Res 2006;34:150-155.
[26]Ye S. Influence of matrix metalloproteinase genotype on cardiovascular disease susceptibility and outcome. Cardiovasc Res 2006;69:636-645.
[27]Tsukahara S, Shinozaki M, Ikari K, Mochizuki T, Inoue E, Tomatsu T, et al. Effect of matrix metalloproteinase-3 functional SNP on serum matrix metalloproteinase-3 level and outcome measures in Japanese RA patients. Rheumatology (Oxford) 2008;7:41-44.
[28]Puddu P, Puddu GM, Zaca F, Muscari A. Endothelial dysfunction in hypertension. Acta Cardio 2000;55:221-232.
[29]Nichols WW, Epstein BJ. Actions of selected cardiovascular hormones on arterial stiffness and wave reflections. Curr Pharm Des 2009;15:304-320.
[30]Medley TL, Cole TJ, Dart AM, Gatzka CD, Kingwell BA. Matrix metalloproteinase-9 genotype luences large artery stiffness through effects on aortic gene and protein expression. Arterioscler Thromb Vase Biol 2004; 24:1479-1484.
[31]Jones GT, Phillips VL, Harris EL, Rossaak JI, van Rij AM. Functional matrix metalloproteinase-9 polymorphism (C-1562T) associated with abdominal aortic aneurysm. J Vase Surg 2003; 38:1363-1367.
[32]Rutter JL, Mitchell TI, Buttice G, Meyers J, Gusella JF, Ozelius LJ, et al. A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter creates an Ets binding site and augments transcription. Cancer Res 1998;58: 5321-5325.
[33]Zhang B, Dhillon S, Geary I, Howell WM, Iannotti F, Day IN, et al. Polymorphisms in matrix metalloproteinase-1,-3,-9, and-12 genes in relation to subarachnoid hemorrhage. Stroke 2001;32:2198-2202.