盐敏感高血压干预新靶标的探索性研究

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作者：张馨予 论文级别：博士 学科专业名称：生物化学与分子生物学 中文关键词：盐敏感 ; 盐敏感高血压 ; eNOS ; LncRNA ; LncRNANOS3AS ; 中药 ; 紫草化腐汤 ; M2b/c调节型巨噬细胞 ; TLR2 ; TLR4 ; MAPKs ; 肥胖悖论 ; 脑卒中预后 ; BMI ; WHR 英文关键词：Salt sensitivty ; Salt-sensitive hypertension ; eNOS ; LncRNA ; LncRNA 英文关键词：NOS3ASTraditional Chinese medicine ; polarization of macrophage subsets ; regulatory macrophages ; TLR2 ; TLR4 ; MAPKsobesity paradox ; Stroke Prognosis ; BMI ; WHR 学位年度：2013 导师：惠汝太 学科代码：071010 学位授予单位：北京协和医学院 论文提交日期：2013-04-01

摘要

目的：高血压是环境、遗传因素及表观遗传调控相互作用引起的复杂性状疾病。盐作为重要的环境因素之一,一直是人们关注的焦点。近百年来人们围绕盐与血压关系进行的研究,基本上确定了盐是高血压最重要的易患因素。但在人群内个体间对盐负荷或限盐却呈现不同的血压反应,即存在盐敏感性问题。盐敏感性是连接盐与高血压的遗传基础,是原发性高血压的一种内表型。研究者们用不同的方法探索导致盐敏感性的易感基因,以期阐明盐敏感性高血压的分子遗传学发病机制。表观遗传控制机制是保证基因的表达可以精确地应对来自机体内外部环境的变化的基础。所以表观遗传学可能是连接环境因素与基因型的桥梁。表观遗传学为我们解释环境因素如何影响个体的基因背景进而产生变异而诱发疾病提供一种可能。虽然已有多个与盐敏感高血压相关的表观遗传调控机制被发现,但基于RNA的表观修饰还未见报道,尤其是已在在心血管疾病中显示出重要的调控功能的长链非编码RNAs (LncRNAs)。研究发现LncRNAs在心血管表观遗传中亦起着重要作用。虽然尚没有LncRNAs与盐敏感高血压直接相关的证据,但是从LncRNAs所调控的靶基因的生物学功能分析提示可能有LncRNAs参与了盐敏感高血压的发生并在其中发挥调控作用。本研究采用候选策略,选取了其所调控的编码基因直接与盐敏感高血压相关的以下三个LncRNA——HOTAIR、 NOS3AS、aHIF,拟从体内(盐敏感高血压动物模型)、体外(人肾小管上皮细胞和人脐静脉内皮细胞)两个水平验证可能参与盐敏感高血压发生的LncRNA.
     方法：我们选用边缘高血压大鼠(borderline hypertensive rat, BHR)作为本研究的动物模型,它是自发性高血压大鼠(spontaneously hypertension rat, SHR)与血压正常的Wistar-Kyoto大鼠(WKY)杂交后的F1代,是一种环境因素诱导的高血压模型,并且鉴于SHR母鼠与WKY母鼠的子代对于环境因素敏感性的不同,我们选用较敏感的SHR母鼠的子代sBHR。5周龄体重、血压相当的sBHR随机分为雌雄各4只的4个实验组：高盐饮食组(high salt diet)、高盐饮食后枸杞干预组(Lycium barbarum L)、正常饮食组(control)、低盐饮食组(low salt diet)。正常饮食4周后(9周龄)给予不同盐浓度纯成分饲料,尾脉搏测压法观察高血压发生情况。待高盐饮食诱导血压升高一周后给予高盐饮食后枸杞干预组具有补肾益精的枸杞(雌鼠10g/天,雄鼠20g/天)4周,以观察饮食能否干预高盐诱导的血压水平,尾脉搏测压法监测血压水平。实验结束后磁珠法分选sBHR肾小管上皮细胞和肾血管内皮细胞,实时荧光定量PCR法(Real-time qPCR)检测三个LncRNA (HOTAIR、NOS3AS、aHIF)和受其调控的编码基因(LSD1、eNOS、 HIF-1α)的表达。体外实验我们选择人脐静脉内皮细胞(HUVEC)和人肾小管细胞(HKC)验证高盐负荷下三个LncRNA (HOTAIR、NOS3AS、aHIF)和受其调控的编码基因(LSD1、eNOS、HIF-1α)的表达。
     结果：给予9周龄的sBHR不同盐浓度纯成分饲料后,高盐饮食12周后,高盐组(high salt diet)和高盐饮食后枸杞干预组(Lycium barbarum L)的血压较正常饮食组明显升高。随后给予高盐饮食后枸杞干预组(Lycium barbarum L)每天20g(雄鼠)/10g(雌鼠)的枸杞,四周后高盐饮食后枸杞干预组(Lycium barbarumL)的血压降至正常水平。但低盐饮食组(low salt diet)的血压水平与正常饮食组(control)的差异没有统计学意义。Real-time qPCR检测磁珠法分选的各组sBHR肾血管内皮细胞LncRNA NOS3AS和编码基因eNOS的表达,结果显示：相对于正常饮食的血压正常组,高盐饮食诱导的高血压组的LncRNA NOS3AS的表达明显上调,但是eNOS的表达却没有变化,表现为血压升高。而高盐饮食后枸杞干预组(Lycium barbarum L)相对于高盐饮食组(high salt diet) LncRNA NOS3AS的表达明显降低,并伴eNOS表达的显著上调,表现血压下降。低盐饮食组(low salt diet) LncRNA NOS3AS和eNOS的表达与正常饮食组(control)相比没有差异,血压水平也没有明显的差别。在高盐负荷(150mM NaCl)刺激下1小时后,HUVEC细胞LncRNA NOS3AS呈一过性地表达上调,而受其转录后调控的编码基因eNOS在高盐负荷刺激6小时后表达有明显的下调。并且在高盐负荷一小时时,加入枸杞多糖(Lycium barbarum polysaccharides, LBP)的HUVEC所表达的LncRNA NOS3AS明显低于未加入LBP的HUVEC.而本研究所涉及的另外两种LncRNA (HOTAIR和aHIF)与高盐负荷及盐敏感高血压的发生没有明显的相关性。
     结论：我们的研究结果显示LncRNA NOS3AS通过下调eNOS mRNA的表达而参与盐敏感高血压的发生。本研究从体内(盐敏感高血压模型)和体外(人脐静脉内皮细胞)两个水平均证实了高盐负荷可诱导LncRNA NOS3AS的表达显著上调。同时eNOS mRNA的表达水平随着LncRNA NOS3AS的上调而下降,随着LncRNA NOS3AS的抑制而上升。而且上调的LncRNA NOS3AS与高盐饮食诱导的血压升高密切相关。并且在高盐负荷下,不论体内试验的sBHR肾血管内皮细胞还是体外实验的人脐静脉内皮细胞的LncRNA NOS3AS的上调始终早于eNOS mRNA水平的下调。提示我们LncRNA NOS3AS不论是在对高盐负荷刺激的应答方面还是反应血压水平方面,都比eNOS mRNA的表达更具敏感性。
     目的：紫草化腐汤,由紫草等十九味中药组成,全方共奏去瘀活血、化腐生肌、祛风解毒、消肿止痛、燥湿敛疮、煨脓长肉之功,在临床上外用于各类创伤感染性创面和难愈性溃疡。而现代医学认为,慢性难愈合性创面的主要特征为持续异常的炎症反应,包括单核／巨噬细胞的持续激活和聚集,以及一系列促炎炎症因子表达的异常升高。因此,紫草化腐汤的药理作用显示出其具有强大的免疫调节功效。虽然现代中药药理学研究已阐明了紫草的抗菌、消炎以及抗肿瘤等药效的分子机制,己明确紫草对多种细菌有明显的抑制作用,且可加强局部血液循环,促进上皮生长,从而起到抗感染、生肌祛腐的功效。但是整个方剂的药理机制并没有被阐明。巨噬细胞是一种具有可塑性和多功能性的细胞群体,通过模式识别受体(TLRs)控制着机体免疫应答,并保持促炎反应和抑炎反应的平衡。因此我们提出假设：紫草化腐汤可通过影响巨噬细胞极化类型的信号转导通路影响其极化方向,从而发挥其消炎止痛、去腐生肌的免疫调节作用。
     方法：我们利用体外培养的THP-1细胞来研究紫草化腐汤对于单核／巨噬系统的影响。首先使用ELISA实验检测在不同浓度的紫草化腐汤(1%,2%及3%(v/v))的作用下,不同时间点,包括TNF-α、TGF-β1、IL-6、IL-8和CCL2在内的几种已经成为治疗各类炎症相关性疾病的干预靶点的细胞因子的分泌情况。接着我们利用real-time qPCR的方法检测了巨噬细胞类型相关的特征性细胞因子的基因表达水平以判断紫草化腐汤诱导巨噬细胞极化的方向。继而检测了参与该过程的TLRs,并且利用有丝分裂原激活蛋白激酶(MAPKs)抑制剂验证了参与紫草化腐汤诱导巨噬细胞极化的信号转导途径。
     结果：紫草化腐汤并不是单纯地抑制M1型巨噬细胞分泌的传统意义上的促炎因子,而是表现出类似于GM-CSF诱导的M2型巨噬细胞的特性：获得了产生TNF-a的能力并且可以低水平的表达IL-6。THP-1细胞在紫草化腐汤的作用下激活TLR4和TLR2途径诱导巨噬细胞极化为M2b/c调节型巨噬细胞,在高表达IL-10的同时低表达IL-12。但是介导这种极化现象的转录途径却是复杂的：IL-8基因的表达经紫草化腐汤诱导后显著增加,并且阻断三种MAPKs中的任何一种激酶都可以抵消紫草化腐汤相关的表达增加,说明紫草化腐汤对IL-8表达的影响是多途径多通路的。但同时,紫草化腐汤却只通过JNK1/2和p38MAPK两种途径促进TGF-β2的表达。
     结论：综上所述,我们的研究发现,紫草化腐汤能够直接诱导巨噬细胞极化为M2b/c调节型巨噬细胞而发挥其消炎止痛、去腐生肌的药理作用,实现了抑制炎症反应、促进坏死的组织细胞的清除、促进血管生成和促进组织愈合。而这个过程是通过上调TLR2和TLR4并激活MAPKs的活性特异性的高表达IL-10、IL-8、CCL2、TGF-β2,同时低表达IL-12、IL-6、TNF-α和TGF-β1而实现的。我们的研究不仅提供了一个基于巨噬细胞极化方向的对抗慢性炎症性相关疾病的干预靶点,更为我们理解和解释众多消炎止痛类的传统中药的药理机制提供了新的切入点。
     目的：超重和肥胖是多种心血管系统疾病,包括脑卒中、高血压病、冠心病和心力衰竭的重要危险因素之一。因此,在心血管系统疾病的一级预防中,控制超重和肥胖是一项重要措施。然而近年的一些研究,尤其是心血管疾病方面的队列研究,却发现体质指数(body mass index, BMI)与患者近期和远期死亡率呈反比,此即所谓的“肥胖悖论”。与其他心血管疾病一样,对于脑卒中的患者来说,控制体重仍是预防脑卒中发生和复发的重要措施,但是与低体重和正常体重患者相比,超重和肥胖的脑卒中患者却拥有较低的死亡率。
     虽然“肥胖悖论”的证据越来越多,但还是受到了质疑。首先,“肥胖悖论”只是一种统计学的相关,目前还不能肯定其间存在因果联系；其次,对肥胖的定义产生偏差。大部分关于“肥胖悖论”的研究,都以WHO推荐的BMI标准作为划定肥胖的标准,而很少测量患者的腰围(WC)、臀围。事实上,研究发现,不同人种的体脂分布不同,应根据不同人种选取相应的BMI截点定义肥胖。并且相比反映身体整体肥胖程度的指标的BMI,反映中心性肥胖的指标,WC、腰臀比(waist to hip ratio, WHR),体重升高比等指标具有更好的预测力。
     面对脑卒中居高不下的致死率和致残率,影响其复发和预后的危险因素仍值得进一步深入地探索和研究,特别是仍然具有争议的“肥胖悖论”提示我们,过度的减肥治疗是否应该慎而为之?本研究针对其他关于脑卒中预后与肥胖相关性分析的研究的缺陷,不仅考虑了人群种族的问题,除应用经典连续变量的四分位法划分BMI区间外,还采用了以BMI作为划定肥胖的中国标准,而且增加了在对于肥胖与心血管疾病风险的研究上具有更好的预测力的WHR这一指标,多角度应证中国人群中脑卒中预后的“肥胖悖论”。
     方法：我们对国家科技部973项目关于脑卒中危险因素的多中心分析研究的数据库进行了再评估。本研究中的所有脑卒中患者同时招募于兖州、西安、重庆、武汉、北京和天津七个临床中心2000-2001年间的住院患者。试验纳入的脑卒中患者只包括以下三种类型：血栓性脑梗死(thrombosis),腔隙性脑梗死(lacunar),脑出血(hemorrhage)。相关诊断必须符合第九版《国际疾病分类》制订的各类脑血管病诊断标准,且经头颅CT和／或MRI证实有梗死灶者——CT (89.8%), MRI (5%),或者两者兼有(5.2%)。在所有被招募的2000例脑卒中患者中,177例患者由于以下诸种原因而最终被排除：缺失明确的诊断(24例),缺失血浆(76例),基因分型不明确(77例)。最终分析的样本大小为1823例,其中807例为血栓性脑梗死(thrombosis),513例为腔隙性脑梗死(lacunar),503例为脑出血(hemorrhage).1823例脑卒中患者按BMI的四分位分类法分为四组：Q1,BMI<21.9kg/m2；Q2,21.9≤BMI<24.2kg/m2；Q3,24.2≤BMI<26.4kg/m2；Q4, BMI≥26.4kg/m2.再根据中国肥胖工作组对我国成人超重、肥胖及中心性肥胖分类的建议,分别以BMI≥24定为超重,BMI≥28定为肥胖,WHR值男性≥0.9,女性≥0.85,称为中心性肥胖。根据以上标准,所有纳入试验的脑卒中患者按BMI分为低体重组(BMI<18.5kg/m2)正常体重组(18.5≤BMI<24kg/m2)、超重组(24.0≤BMI<28kg/m2)和肥胖组(BMI≥28.0kg/m2);按WHR分为正常组(男性WHR<0.90,女性WHR<0.85)和中心性肥胖组(男性WHR≥0.90,女性WHR≥0.85)。以患者入组时间为起点,死亡发生时间为终点。风险比(hazard ratios,HR)以及95%可信区间(95％confidence intervals,CI)通过单因素及多因素Cox回归模型进行计算。并对不同脑卒中类型进行分层评估。所有统计分析均通过SPSS14.1版SPSS软件实施,以p<0.05表示差异有统计学意义。
     结果：最终分析的样本大小为1823例,患者年平均60.3±9.4岁,其中男性占63.5%。1823例脑卒中患者按BMI的四分位分类法分为四组：Q1～Q4,BMI在Q3组(24.2≤BMI<26.4kg/m2)的脑卒中发作后的患者,其全死因死亡风险最低(HR:0.77,CI:0.66-0.90,p=0.001),其BMI与全死因死亡风险之间,呈U型曲线。同时经过亚组分析后发现,BMI在此范围的血栓性脑梗死患者,其全因死亡风险(HR:0.70,95％CI:0.55-0.89,p=0.003)和心血管事件相关死亡风险(HR:0.67,95％CI:0.47-0.95,p=0.023)均为最低。随后我们就按照中国肥胖工作组对我国成人超重、肥胖分类的建议,分别以BMI>24定为超重,BMI≥28定为肥胖。结果显示,在校正了所有混杂因素后,相对于体重正常组,超重组(HR:0.75:95％CI:0.58-0.96,p=0.021)的全因死亡风险降低。而低体重组(HR:1.70'95％CI:1.09-2.65,p=0.02)的全因死亡风险增加。在经过亚组分析后发现体重超重组的血栓性脑梗死患者,无论是其全因死亡风险(HR:0.65；95％CI:0.45-0.93,p=0.020)还是心血管事件相关的死亡风险(HR:0.56；95％CI:0.32.0.98,p=0.042)均降低。而对于腔隙性脑梗死患者来说,其低体重组的全因死亡风险(HR:6.11;95％CI:1.65-22.60,p=0.007)和心血管事件相关的死亡风险(HR:9.91;95％CI:1.59-61.62,p=0.014)明显增加。本研究又进一步采用了中国肥胖工作组对我国成人中心性肥胖分类的建议,分别以WHR值男性≥0.9,女性≥0.85定义中心性肥胖。根据以上标准,中心性肥胖的脑卒中患者,无论是其全因死亡风险(HR:0.73；95％CI:0.58-0.91,p=0.006)还是心血管事件相关的死亡风险(HR:0.65；95％CI:0.48-0.89,p=0.008)相对于正常组都是降低的。其中中心性肥胖的血栓性脑梗死患者的全因死亡风险低于正常组(HR:0.71；95％CI:0.51-0.98,p=0.040),而中心性肥胖的腔隙性脑梗死(HR:0.45；95％CI:0.22-0.94,p=0.032)和脑出血的患者(HR:0.59；95％CI:0.36-0.98,p=0.039)的心血管事件相关的死亡风险低于正常组。
     结论：综合我们的研究结果可以发现,中国人群的脑卒中预后同样存在着“肥胖悖论”,即减轻体重、防治肥胖虽可以减少脑卒中的发生,但是体重下降后脑卒中患者的预后却得不到改善,甚至反而更差。尤其相对于体重正常的脑卒中患者,体重超重／中心性肥胖的患者的全因死亡风险更低。
Objective:Hypertension is a major public health challenge due to its high prevalence and concomitant increase in the risk for cardiovascular disease (CVD) and all-cause mortality. As a complex trait, hypertension is influenced by multiple environmental and genetic determinants, as well as their interactions. Among environmental determinants, dietary sodium intake is the most common and important risk factor for hypertension. However, there is substantial evidence suggesting that BP responses to dietary sodium intake vary considerably among individuals, a phenomenon described as salt sensitivity of blood pressure (BP). Elucidation of the genetic contribution to salt sensitivity provides important information regarding how genes and dietary sodium interact to influence BP. Salt-sensitive hypertension is, at least in part, under genetic control but the underlying genetic mechanisms are not fully clarified. Epigenetic control mechanisms may additively or synergistically interact to precisely respond to internal and external environmental cues. LncRNAs, tentatively defined as noncoding RNAs more than200nt in length, are characterized by the complexity and diversity of their sequences and mechanisms of action. A handful of studies have implicated LncRNAs in a variety of disease states. However, there are only preliminary studies on the role of LncRNAs in regulating genes that have been associated with salt-sensitive hypertension. In fact, there were virtually no published data on the overall pathophysiological contributions of LncRNAs to salt-sensitive hypertension. In this study, we identified the effects of these three LncRNAs, HOTAH、NOS3AS、aHIF, in the development of salt-sensitive hypertension in vivo and in vitro.
     Methods:We chose borderline hypertensive rat (BHR) as the animal model of this study. It is a kind of hypertension model which was induced by environmental factors, which is the F1generations of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Since the sensitivity for different environmental factors is determined by mother of offspring, we select the progenies of SHR rats who is more sensitive.5weeks old sBHR randomly divided into four groups (four males and four females):high salt diet, high salt diet and Lycium barbarum L., control, low salt diet. After4weeks of normal diet, pure component feed which has different salt concentration was given to the four groups.
     The systolic blood pressure was monitored by tail cuff method. The renal endothelial and epithelial cells of sBHR were separated by magnetic bead coated with specific antibody. The expression of the LncRNAs (HOTAIR、NOS3AS、aHIF) and the coding genes(LSD1、eNOS、HIF-la) which were regulated by the LncRNAs were determined by real-time qPCR. They also were identified by real-time qPCR from human umbilical vein endothelial cells (HUVEC) and renal tubular cells (HKC) which were under high salt load In vitro.
     Results:We found that the blood pressure of high salt diet group and Lycium barbarum L. group was higher than that of control after having high salt diet for12weeks. Then the blood of Lycium barbarum L. group returned to normal after intervention of Lycium barbarum L. And the high salt diet exerts significant influence on the upregulation of LncRNA NOS3AS which was association with the increased blood level. The expression of eNOS mRNA was decreasing when the LncRNA NOS3AS was downregulation in the renal endothelial cells from Lycium barbarum L. group. The expression of LncRNA NOS3AS from HUVEC cells was increasing upon high salt treatment150mM NaC1). And the upregulation of LncRNA NOS3AS was earlier than the downregulation of eNOS mRNA. Importantly, Lycium barbarum polysaccharides (LBP) functionally regulated LncRNA NOS3A expression during high salt treatment(150mM NaCl), since LBP blunted it's rising during prolonged high salt treatment. But the other LncRNA (HOTAIR and aHIF) had no obvious correlation with salt sensitive hypertension.
     Conclusions:The upregulation of LncRNA NOS3AS was association with develpoment of salt sensitive hypertension by regulating eNOS mRNA post-transcriptionally during high salt load in vivo and in vitro.
     Objective:As a traditional Chinese herbal formula composed of19herbs, Zicao-Huafu-Tang (ZHT) has been external used as a high efficient anti-inflammatory and analgesic medicine to treat inflammatory diseases such as skin trauma, diabetic ulcers, toothache pain, haemorrhoids, as well as cancers, indicating its general immunomodulatory effects. The mechanism of its wide pharmacological effects has not been explored. Toll-like receptors signaling and MAPKs activation have been known to modulate the inflammatory process in macrophage. We hypothesized that the favorable effects of ZHT on inflammation maybe through modulating this signaling pathway.
     Methods:We investigated the immunomodulatory mechanism of ZHT in Human monocyte cell line (THP-1) which was treated with ZHT in vitro, since macrophages are essential for innate immunity and play a central role in inflammation. Our hypothesis was tested in THP-1which was treated with ZHT at dosage1%,2%and3%(v/v)respectively, for24hours,48hours, and72hours. Cytokines, including tumour necrosis factor-a (TNF-a), Transforming growth factor-β1(TGF-β1), interleukin (IL)-6、IL-8and chemokine (C-C motif) ligand2(CCL2) in the cell culture supernatant, were determined by ELISA. The expression profile of M2b/c regulatory macrophages specific cytokines (IL-12low and IL-10high) and Toll-like receptors, the key players in immunomodulatory signaling pathway, were determined by real-time qPCR.
     Results:We found that ZHT exerts significant influence on TLR2/TLR4mediated polarization of macrophage subsets toward M2b/c regulatory macrophage phenotype. This may explain, at least in part, the favorable effects of ZHT on immune response, supported by evidence that more interleukin (IL)-10, IL-8, chemokine (C-C motif) ligand2(CCL2), Transforming growth factor-β2(TGF-β2), but less IL-12, IL-6, tumour necrosis factor-α (TNF-α), TGF-β1were released upon ZHT treatment. The underlying intracellular regulatory signaling mechanisms are complex since different cytokine and chemokine are regulated by different signaling intermediate activation. Our results support that MAPK activity is necessary for expression of IL-8and TGF-β2, while PKA activity is also necessary for expression of IL-10and TNF-α from other study reports.
     The main task of M2b/c regulatory macrophages is to dampen and control immune responses through an IL-12low and IL-10high expression profile and thereby contributing to the resolution of inflammatory responses. The M2b/c regulatory macrophages subpopulations are generated by different stimuli which need two stimuli to induce their anti-inflammatory activity. The first signal (for example, immune complexes, prostaglandins, adenosine or apoptotic cells) generally has little or no stimulatory function on its own. However, when combined with a second stimulus, such as a TLR ligands, the two signals reprogramme macrophages to produce IL-10, the production of which is the most important and reliable characteristic of regulatory macrophages. This is in good agreement with our observations here, that ZHT enhances IL-10expression but limits IL-12production. Of greater interest in the present study is that ZHT can induce M2b/c regulatory macrophages polarized states directly rather than reprogramming with the two signals reprogramme.
     Conclusions:ZHT not only suppressed inflammatory process, but also activated regulatory macrophages and facilitated inflammation resolution through modulating TLR2and TLR4signaling with MAPKs activation. These findings suggest that ZHT may offer some clinical advantages over glucocorticoids because it is likely to trigger activation of M2b/c regulatory macrophages that could be deemed proresolution but less levels of type1cytokines like TNF-a and IL-12.
     Objective:Contrary to common knowledge of the deleterious effects of obesity, it has been reported that obese stroke survivors are likely to have lower mortality than their underweight counterparts. Such a paradoxical phenomenon of lower mortality or risk of recurrent vascular disease in overweight or obese patients with established disease was coined the obesity paradox. However, in spite of accumulating reports on populations with various diseases, there are still doubts about the obesity paradox. Since the criteria for defining obesity and metabolic syndrome need to consider the influence of ethnicity, it is necessary to demonstrate the obesity paradox of stroke prognosis in Chinese population. In addition, the use of both body mass index (BMI) as an index of obesity has been challenged from recent studies as being not truely representative of total fat distribution. In this context, we evaluated the association between obesity and survival in patients with first-ever stroke by using BMI and waist to hip ratio (WHR) as indicators of obesity.
     Methods:We reviewed data from the multicenter study for assessment of risk factors of stroke sponsored by the Ministry of Science and Technology of China (973project). Initially,2000cases were recruited. Before data assessment,177subjects were excluded at different experimental stages because of lack of a definite diagnosis (24cases), absence of plasma (76cases), and failure of genotyping (77cases). Among the1823cases,807were diagnosed as thrombosis;513as lacunar; and503as hemorrhage. Participants were grouped into quartiles of BMI (Q1to Q4). The standards of BMI in adults in China was18.5≤BMI<24kg/m2for normal,24.0≤BMI<28kg/m2for overweight and BMI>28.0for obesity, then the participants were further classified as low weight, normal weight, overweight and obesity respectively. And the Chinese-specific of WHR cutoff is0.90for men and0.85for women, then the participants were divided into2groups according to WHR:normal weight (WHR<0.90for man, WHR<0.85for women), and obese (WHR>0.90for man, WHR≥0.85for women). Overall survival during follow-up was the primary end point. Mortality was assessed by Cox proportional hazard analysis and hazard ratios (HR) and95%confidence intervals (CI) are presented.
     Results:According to BMI (Q1to Q4), compared to controls in the lowest quartile, all-cause mortality risk was lower in the BMI Q3[24.2≤BMI<26.4kg/m2, hazard ratio (HR):0.77,95%confidence interval (CI):0.66-0.90),p=0.001]. Of1823eligible subjects,231(13%) were obese. After adjusting for confounders, compared with the normal weight patients, the lower all-cause mortality risk was in overweight patients (HR:0.75;95%CI:0.58-0.96, p=0.021), but low weight patients had higher all-cause mortality risk(HR:1.70;95%CI:1.09-2.65, p=0.02). And being overweight patients of thrombosis was associated with lower all-cause mortality risk (HR:0.65;95%CI:0.45-0.93,p=0.020) and lower risk of death caused by major vascular event (HR:0.56;95%CI:0.32-0.98, p=0.042). being low weight patients of lacunar was associated with the higher all-cause mortality risk (HR:6.11;95%CI:1.65-22.60,p=0.007) and higher risk of death caused by major vascular event (HR:9.91;95%CI:1.59-61.62, p=0.014). Based on WHR, after adjusting for confounders, compared with the normal group, being central obesity (HR:0.73;95%CI:0.58-0.91,p=0.006) was not only associated with decreased all-cause mortality risk, but also associated with lower risk of death caused by major vascular event(HR:0.65;95%CI:0.48-0.89,p=0.008). And being central obesity patients of lacunar (HR:0.45;95%CI:0.22-0.94,p=0.032) and hemorrhage (HR:0.59;95%CI:0.36-0.98,p=0.039) was associated with lower risk of death caused by major vascular event.
     Conclusions:based on the standards of BMI and WHR in China, obese and overweight stroke patients have significantly better survival rates compared to their leaner counterparts, supporting the widely held notion of the existence of a cardiovascular "obesity paradox."

引文

[1]Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension:analysis of worldwide data. Lancet. Jan 15-212005;365(9455):217-223.
    [2]Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension. Cell. Feb 23 2001;104(4):545-556.
    [3]Ferrari P, Lovati E, Frey FJ. The role of the 11beta-hydroxysteroid dehydrogenase type 2 in human hypertension. J Hypertens. Mar 2000;18(3):241-248.
    [4]Geller DS, Zhang J, Wisgerhof MV, Shackleton C, Kashgarian M, Lifton RP. A novel form of human mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab. Aug 2008;93(8):3117-3123.
    [5]Choi M, Scholl UI, Yue P, et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science. Feb 112011;331(6018):768-772.
    [6]Snyder PM, Price MP, McDonald FJ, et al. Mechanism by which Liddle's syndrome mutations increase activity of a human epithelial Na+ channel. Cell. Dec 15 1995;83(6):969-978.
    [7]Nozu K, Inagaki T, Fu XJ, et al. Molecular analysis of digenic inheritance in Bartter syndrome with sensorineural deafness. J Med Genet. Mar 2008;45(3):182-186.
    [8]Chang SS, Grunder S, Hanukoglu A, et al. Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1. Nat Genet. Mar 1996;12(3):248-253.
    [9]Kelly TN, He J. Genomic epidemiology of blood pressure salt sensitivity. J Hypertens. May 2012;30(5):861-873.
    [10]Friso S, Pizzolo F, Choi SW, et al. Epigenetic control of 11 beta-hydroxysteroid dehydrogenase 2 gene promoter is related to human hypertension. Atherosclerosis. Aug 2008;199(2):323-327.
    [11]Zhang D, Yu ZY, Cruz P, Kong Q, Li S, Kone BC. Epigenetics and the control of epithelial sodium channel expression in collecting duct. Kidney Int. Feb 2009;75(3):260-267.
    [12]Bogdarina I, Welham S, King PJ, Burns SP, Clark AJL. Epigenetic Modification of the Renin-Angiotensin System in the Fetal Programming of Hypertension. Circulation Research. 2007;100(4):520-526.
    [13]Mu S, Shimosawa T, Ogura S, et al. Epigenetic modulation of the renal β-adrenergic-WNK4 pathway in salt-sensitive hypertension. Nature Medicine.2011;17(5):573-580.
    [14]Williams JS, Chamarthi B, Goodarzi MO, et al. Lysine-Specific Demethylase 1:An Epigenetic Regulator of Salt-Sensitive Hypertension. Am J Hypertens. Apr 26 2012.
    [15]Lorenzen JM, Martino F, Thum T. Epigenetic modifications in cardiovascular disease. Basic Res Cardiol. Mar 2012;107(2):245.
    [16]Visel A, Zhu Y, May D, et al. Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice. Nature. Mar 18 2010;464(7287):409-412.
    [17]Ishii N, Ozaki K, Sato H, et al. Identification of a novel non-coding RNA, MIAT, that confers risk of myocardial infarction. J Hum Genet.2006;51(12):1087-1099.
    [18]Colley SM, Leedman PJ. Steroid Receptor RNA Activator-A nuclear receptor coregulator with multiple partners:Insights and challenges. Biochimie. Nov 2011;93(11):1966-1972.
    [19]Dharap A, Nakka VP, Vemuganti R. Effect of focal ischemia on long noncoding RNAs. Stroke. Oct 2012;43(10):2800-2802.
    [20]Titze J, Machnik A. Sodium sensing in the interstitium and relationship to hypertension. Curr Opin Nephrol Hypertens. Jul 2010;19(4):385-392.
    [21]Machnik A, Neuhofer W, Jantsch J, et al. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat Med. May 2009;15(5):545-552.
    [22]Machnik A, Dahlmann A, Kopp C, et al. Mononuclear phagocyte system depletion blocks interstitial tonicity-responsive enhancer binding protein/vascular endothelial growth factor C expression and induces salt-sensitive hypertension in rats. Hypertension. Mar 2010;55(3):755-761.
    [23]Lee AS, Lee JE, Jung YJ, et al. Vascular endothelial growth factor-C and -D are involved in lymphangiogenesis in mouse unilateral ureteral obstruction. Kidney Int. Jan 2013;83(1):50-62.
    [24]Hu D, Fukuhara A, Miyata Y, et al. Adiponectin regulates vascular endothelial growth factor-C expression in macrophages via Syk-ERK pathway. PLoS One.2013;8(2):e56071.
    [25]Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. Jan 2007;117(1):175-184.
    [26]Coenen KR, Gruen ML, Chait A, Hasty AH. Diet-induced increases in adiposity, but not plasma lipids, promote macrophage infiltration into white adipose tissue. Diabetes. Mar 2007;56(3):564-573.
    [27]Neels JG, Olefsky JM. Inflamed fat:what starts the fire? J Clin Invest. Jan 2006;116(1):33-35.
    [28]Uretsky S, Messerli FH, Bangalore S, et al. Obesity paradox in patients with hypertension and coronary artery disease. Am J Med. Oct 2007;120(10):863-870.
    [1]Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension:analysis of worldwide data. Lancet. Jan 15-212005;365(9455):217-223.
    [2]Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors,2001:systematic analysis of population health data. Lancet. May 27 2006;367(9524):1747-1757.
    [3]Danaei G, Finucane MM, Lin JK, et al. National, regional, and global trends in systolic blood pressure since 1980:systematic analysis of health examination surveys and epidemiological studies with 786 country-years and 5.4 million participants. Lancet. Feb 12 2011;377(9765):568-577.
    [4]Kato N, Takeuchi F, Tabara Y, et al. Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians. Nat Genet. Jun 2011;43(6):531-538.
    [5]Levy D, Ehret GB, Rice K, et al. Genome-wide association study of blood pressure and hypertension. Nat Genet. Jun 2009;41(6):677-687.
    [6]Newton-Cheh C, Johnson T, Gateva V, et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet. Jun 2009;41(6):666-676.
    [7]Whelton PK, He J, Appel LJ, et al. Primary prevention of hypertension:clinical and public health advisory from The National High Blood Pressure Education Program. JAMA. Oct 16 2002;288(15):1882-1888.
    [8]GenSalt:rationale, design, methods and baseline characteristics of study participants.J Hum Hypertens. Aug 2007;21(8):639-646.
    [9]Meneton P, Jeunemaitre X, de Wardener HE, MacGregor GA. Links between dietary salt intake, renal salt handling, blood pressure, and cardiovascular diseases. Physiol Rev. Apr 2005;85(2):679-715.
    [10]Luft FC, Weinberger MH. Heterogeneous responses to changes in dietary salt intake: the salt-sensitivity paradigm. Am J Clin Nutr. Feb 1997;65(2 Suppl):612S-617S.
    [11]Chen J, Gu D, Huang J, et al. Metabolic syndrome and salt sensitivity of blood pressure in non-diabetic people in China:a dietary intervention study. Lancet. Mar 7 2009;373(9666):829-835.
    [12]Kelly TN, He J. Genomic epidemiology of blood pressure salt sensitivity. J Hypertens. May 2012;30(5):861-873.
    [13]Luft FC, Grim CE, Willis LR, Higgins JT, Jr., Weinberger MH. Natriuretic response to saline infusion in normotensive and hypertensive man. The role of renin suppression in exaggerated natriuresis. Circulation. May 1977;55(5):779-784.
    [14]Kawasaki T, Delea CS, Bartter FC, Smith H. The effect of high-sodium and low-sodium intakes on blood pressure and other related variables in human subjects with idiopathic hypertension. Am JMed. Feb 1978;64(2):193-198.
    [15]He J, Gu D, Chen J, et al. Gender difference in blood pressure responses to dietary sodium intervention in the GenSalt study. J Hypertens. Jan 2009;27(1):48-54.
    [16]牟建军.盐与高血压研究进展.中国医学前沿杂志(电了版).2011；3(2)：22-25.
    [17]Rodriguez-Iturbe B, Romero F, Johnson RJ. Pathophysiological mechanisms of salt-dependent hypertension. Am J Kidney Dis. Oct 2007;50(4):655-672.
    [18]Zhao Q, Gu D, Hixson JE, et al. Common variants in epithelial sodium channel genes contribute to salt sensitivity of blood pressure:The GenSalt study. Circ Cardiovasc Genet. Aug 1 2011;4(4):375-380.
    [19]DiBona GF. Sympathetic nervous system and the kidney in hypertension. Curr Opin Nephrol Hypertens. Mar 2002;11(2):197-200.
    [20]Grassi G, Bertoli S, Seravalle G. Sympathetic nervous system:role in hypertension and in chronic kidney disease. Curr Opin Nephrol Hypertens. Jan 2012;21(1):46-51.
    [21]Castejon AM, Bracero J, Hoffmann IS, Alfieri AB, Cubeddu LX. NAD(P)H oxidase p22phox gene C242T polymorphism, nitric oxide production, salt sensitivity and cardiovascular risk factors in Hispanics. J Hum Hypertens. Oct 2006;20(10):772-779.
    [22]Miyaki K, Tohyama S, Murata M, et al. Salt intake affects the relation between hypertension and the T-786C polymorphism in the endothelial nitric oxide synthase gene. Am J Hypertens. Dec 2005,18(12 Pt 1):1556-1562.
    [23]Caprioli J, Mele C, Mossali C, et al. Polymorphisms of EDNRB, ATG, and ACE genes in salt-sensitive hypertension. Can JPhysiol Pharmacol. Aug 2008;86(8):505-510.
    [24]Gu D, Rice T, Wang S, et al. Heritability of blood pressure responses to dietary sodium and potassium intake in a Chinese population. Hypertension. Jul 2007;50(1):116-122.
    [25]Miller JZ, Weinberger MH, Christian JC, Daugherty SA. Familial resemblance in the blood pressure response to sodium restriction. Am J Epidemiol. Nov 1987;126(5):822-830.
    [26]Svetkey LP, McKeown SP, Wilson AF. Heritability of salt sensitivity in black Americans. Hypertension. Nov 1996;28(5):854-858.
    [27]Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension. Cell. Feb 23 2001;104(4):545-556.
    [28]Ferrari P, Lovati E, Frey FJ. The role of the llbeta-hydroxy steroid dehydrogenase type 2 in human hypertension. J Hypertens. Mar 2000;18(3):241-248.
    [29]Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med. Aug 21 2003;349(8):776-788.
    [30]Geller DS, Zhang J, Wisgerhof MV, Shackleton C, Kashgarian M, Lifton RP. A novel form of human mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab. Aug 2008;93(8):3117-3123.
    [31]Choi M, Scholl UI, Yue P, et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science. Feb 112011;331(6018):768-772.
    [32]Snyder PM, Price MP, McDonald FJ, et al. Mechanism by which Liddle's syndrome mutations increase activity of a human epithelial Na+ channel. Cell. Dec 151995;83(6):969-978.
    [33]Wilson FH, Disse-Nicodeme S, Choate KA, et al. Human hypertension caused by mutations in WNK kinases. Science. Aug 10 2001;293(5532):1107-1112.
    [34]Nozu K, Inagaki T, Fu XJ, et al. Molecular analysis of digenic inheritance in Bartter syndrome with sensorineural deafness. J Med Genet. Mar 2008;45(3):182-186.
    [35]Chang SS, Grunder S, Hanukoglu A, et al. Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1. Nat Genet. Mar 1996;12(3):248-253.
    [36]Brand SM. Genetics, genomics and other molecular approaches:example of salt-sensitive hypertension. JHypertens. May 2012;30(5):877-879.
    [37]Citterio L, Lanzani C, Manunta P. Polymorphisms, hypertension and thiazide diuretics. Pharmacogenomics. Nov 2011;12(11):1587-1604.
    [38]Hamrefors V, Sjogren M, Almgren P, et al. Pharmacogenetic implications for eight common blood pressure-associated single-nucleotide polymorphisms. J Hypertens. Jun 2012;30(6):1151-1160.
    [39]Stephens KE, Miaskowski CA, Levine JD, Pullinger CR, Aouizerat BE. Epigenetic Regulation and Measurement of Epigenetic Changes. Biol Res Nurs. Jun 3 2012.
    [40]Schleithoff C, Voelter-Mahlknecht S, Dahmke IN, Mahlknecht U. On the epigenetics of vascular regulation and disease. Clin Epigenetics.2012;4(1):7.
    [41]Lorenzen JM, Martino F, Thum T. Epigenetic modifications in cardiovascular disease. Basic Res Cardiol. Mar 2012;107(2):245.
    [42]Friso S, Pizzolo F, Choi SW, et al. Epigenetic control of 11 beta-hydroxysteroid dehydrogenase 2 gene promoter is related to human hypertension. Atherosclerosis. Aug 2008;199(2):323-327.
    [43]Zhang D, Yu ZY, Cruz P, Kong Q, Li S, Kone BC. Epigenetics and the control of epithelial sodium channel expression in collecting duct. Kidney Int. Feb 2009;75(3):260-267.
    [44]Bogdarina I, Welham S, King PJ, Burns SP, Clark AJL. Epigenetic Modification of the Renin-Angiotensin System in the Fetal Programming of Hypertension. Circulation Research. 2007;100(4):520-526.
    [45]Mu S, Shimosawa T, Ogura S, et al. Epigenetic modulation of the renal β-adrenergic-WNK4 pathway in salt-sensitive hypertension. Nature Medicine.2011;17(5):573-580.
    [46]Williams JS, Chamarthi B, Goodarzi MO, et al. Lysine-Specific Demethylase 1:An Epigenetic Regulator of Salt-Sensitive Hypertension. Am J Hypertens. Apr 26 2012.
    [47]Wapinski O, Chang HY. Long noncoding RNAs and human disease. Trends Cell Biol. Jun 2011;21(6):354-361.
    [48]Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell. Sep 16 2011;43(6):904-914.
    [49]Guttman M, Amit I, Garber M, et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature. Mar 12 2009;458(7235):223-227.
    [50]Rinn JL, Chang HY. Genome Regulation by Long Noncoding RNAs. Annu Rev Biochem. Jul 7 2012;81:145-166.
    [51]Wang XQ, Crutchley JL, Dostie J. Shaping the Genome with Non-Coding RNAs. Curr Genomics. Aug 2011;12(5):307-321.
    [52]Visel A, Zhu Y, May D, et al. Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice. Nature. Mar 18 2010;464(7287):409-412.
    [53]Ishii N, Ozaki K, Sato H, et al. Identification of a novel non-coding RNA, MIAT, that confers risk of myocardial infarction. J Hum Genet.2006;51(12):1087-1099.
    [54]Colley SM, Leedman PJ. Steroid Receptor RNA Activator-A nuclear receptor coregulator with multiple partners:Insights and challenges. Biochimie. Nov 2011;93(11):1966-1972.
    [55]Dharap A, Nakka VP, Vemuganti R. Effect of focal ischemia on long noncoding RNAs. Stroke. Oct 2012;43(10):2800-2802.
    [56]Moran I, Akerman I, van de Bunt M, et al. Human beta cell transcriptome analysis uncovers LncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes. Cell Metab. Oct 3 2012;16(4):435-448.
    [57]Tsai MC, Manor O, Wan Y, et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science. Aug 6 2010;329(5992):689-693.
    [58]Robb GB, Carson AR, Tai SC, et al. Post-transcriptional regulation of endothelial nitric-oxide synthase by an overlapping antisense mRNA transcript. J Biol Chem. Sep 3 2004;279(36):37982-37996.
    [59]Thrash-Bingham CA, Tartof KD. aHIF:a natural antisense transcript overexpressed in human renal cancer and during hypoxia. J Natl Cancer Inst. Jan 20 1999;91(2):143-151.
    [60]Zhu Q, Wang Z, Xia M, Li PL, Zhang F, Li N. Overexpression of HIF-lalpha transgene in the renal medulla attenuated salt sensitive hypertension in Dahl S rats. Biochim Biophys Acta. Jun 2012;1822(6):936-941.
    [61]Li K, Blum Y, Verma A, et al. A noncoding antisense RNA in tie-1 locus regulates tie-1 function in vivo. Blood. Jan 7 2010;115(1):133-139.
    [62]Henke N, Schmidt-Ullrich R, Dechend R, et al. Vascular endothelial cell-specific NF-kappaB suppression attenuates hypertension-induced renal damage. Circ Res. Aug 3 2007;101(3):268-276.
    [63]Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. Jun 10 1999;399(6736):601-605.
    [64]Forte P, Copland M, Smith LM, Milne E, Sutherland J, Benjamin N. Basal nitric oxide synthesis in essential hypertension. Lancet. Mar 22 1997;349(9055):837-842.
    [65]Huang PL, Huang Z, Mashimo H, et al. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature. Sep 21 1995;377(6546):239-242.
    [66]Dengel DR, Brown MD, Ferrell RE, Reynolds TH, Supiano MA. A preliminary study on T-786C endothelial nitric oxide synthase gene and renal hemodynamic and blood pressure responses to dietary sodium. PhysiolRes.2007;56(4):393-401.
    [67]Li N, Chen L, Yi F, Xia M, Li PL. Salt-sensitive hypertension induced by decoy of transcription factor hypoxia-inducible factor-lalpha in the renal medulla. Circ Res. May 9 2008;102(9):1101-1108.
    [68]Sanders PW. Salt intake, endothelial cell signaling, and progression of kidney disease. Hypertension. Feb 2004;43(2):142-146.
    [69]Oberleithner H, Peters W, Kusche-Vihrog K, et al. Salt overload damages the glycocalyx sodium barrier of vascular endothelium. Pflugers Arch. Oct 2011;462(4):519-528.
    [70]Korte S, Wiesinger A, Straeter AS, Peters W, Oberleithner H, Kusche-Vihrog K. Firewall function of the endothelial glycocalyx in the regulation of sodium homeostasis. Pflugers Arch. Feb 2012;463(2):269-278.
    [71]Sato TN, Tozawa Y, Deutsch U, et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature. Jul 6 1995;376(6535):70-74.
    [72]陈庆伟,陈志桃.枸杞多糖药理作用研究进展.海峡药学.2005；17(4)：4-7.
    [73]汪建龙.枸杞多糖药理作用的研究进展.时珍国医国药.2005；16(10)：1032-1033.
    [74]潘正军,张晓蕾,周建武,王建成.枸杞多糖对实验性高血压妊娠小鼠血压和胎鼠发育的影响.生殖与避孕2009；29(2)：70-70.
    [75]Tuomilehto J, Jousilahti P, Rastenyte D, et al. Urinary sodium excretion and cardiovascular mortality in Finland:a prospective study. Lancet. Mar 17 2001;357(9259):848-851.
    [76]Morimoto A, Uzu T, Fujii T, et al. Sodium sensitivity and cardiovascular events in patients with essential hypertension. Lancet. Dec 13 1997;350(9093):1734-1737.
    [77]Grover-Paez F, Zavalza-Gomez AB. Endothelial dysfunction and cardiovascular risk factors. Diabetes Res Clin Pract. Apr 2009;84(1):1-10.
    [78]Ross R. The pathogenesis of atherosclerosis:a perspective for the 1990s. Nature. Apr 29 1993;362(6423):801-809.
    [79]Gonzalez MA, Selwyn AP. Endothelial function, inflammation, and prognosis in cardiovascular disease. Am JMed. Dec 8 2003;115 Suppl 8A:99S-106S.
    [80]Nadar S, Blann AD, Lip GY. Endothelial dysfunction:methods of assessment and application to hypertension. Curr Pharm Des.2004;10(29):3591-3605.
    [81]Liu FQ, Mu JJ, Liu ZQ, et al. Endothelial dysfunction in normotensive salt-sensitive subjects. J Hum Hypertens. Apr 2012;26(4):247-252.
    [82]Forstermann U, Munzel T. Endothelial nitric oxide synthase in vascular disease:from marvel to menace. Circulation. Apr 4 2006; 113(13):1708-1714.
    [83]Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthases:structure, function and inhibition. Biochem J. Aug 1 2001;357(Pt 3):593-615.
    [84]Weber M, Hagedorn CH, Harrison DG, Searles CD. Laminar shear stress and 3'polyadenylation of eNOS mRNA. Circ Res. Jun 10 2005;96(11):1161-1168.
    [85]Searles CD. Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression. Am JPhysiol Cell Physiol. Nov 2006;291(5):C803-816.
    [86]Yan G, You B, Chen SP, Liao JK, Sun J. Tumor necrosis factor-alpha downregulates endothelial nitric oxide synthase mRNA stability via translation elongation factor 1-alpha 1. Circ Res. Sep 12 2008;103(6):591-597.
    [87]Fish JE, Matouk CC, Yeboah E, et al. Hypoxia-inducible expression of a natural cis-antisense transcript inhibits endothelial nitric-oxide synthase. J Biol Chem. May 25 2007;282(21):15652-15666.
    [88]Yang Z, Kaye DM. Mechanistic insights into the link between a polymorphism of the 3'UTR of the SLC7A1 gene and hypertension. Hum Mutat. Mar 2009;30(3):328-333.
    [89]Naraba H, Iwai N. Assessment of the microRNA system in salt-sensitive hypertension. Hypertens Res. Oct 2005;28(10):819-826.
    [90]Zhao J, Sinclair J, Houghton J, Bolton E, Bradley A, Lever A. Cytomegalovirus beta2.7 RNA transcript protects endothelial cells against apoptosis during ischemia/reperfusion injury. J Heart Lung Transplant. Mar 2010;29(3):342-345.
    [91]Yan B, Wang Z. Long Noncoding RNA:Its Physiological and Pathological Roles. DNA Cell Biol. May 21 2012.
    [1]Trengove NJ, Bielefeldt-Ohmann H, Stacey MC. Mitogenic activity and cytokine levels in non-healing and healing chronic leg ulcers. Wound Repair Regen. Jan-Feb 2000;8(1):13-25.
    [2]Hsiao CY, Tsai TH, Chak KF. The molecular basis of wound healing processes induced by lithospermi radix:a proteomics and biochemical analysis. Evid Based Complement Alternat Med. 2012;2012:508972.
    [3]van der Wal AC, Das PK, Tigges AJ, Becker AE. Macrophage differentiation in atherosclerosis. An in situ immunohistochemical analysis in humans. Am JPathol. Jul 1992;141(1):161-168.
    [4]Gordon S, Martinez FO. Alternative activation of macrophages:mechanism and functions. Immunity. May 28 2010;32(5):593-604.
    [5]Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. Dec 2008;8(12):958-969.
    [6]Sica A, Mantovani A. Macrophage plasticity and polarization:in vivo veritas. J Clin Invest. Mar 1 2012;122(3):787-795.
    [7]Gordon S. Alternative activation of macrophages. Nat Rev Immunol. Jan 2003;3(1):23-35.
    [8]Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation and polarization. Front Biosci. 2008;13:453-461.
    [9]Hesse M, Modolell M, La Flamme AC, et al. Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo:granulomatous pathology is shaped by the pattern of L-arginine metabolism. J Immunol. Dec 1 2001;167(11):6533-6544.
    [10]Couper KN, Blount DG, Riley EM. IL-10:the master regulator of immunity to infection. J Immunol. May 1 2008;180(9):5771-5777.
    [11]Hoeksema MA, Stoger JL, de Winther MP. Molecular pathways regulating macrophage polarization: implications for atherosclerosis. Curr Atheroscler Rep. Jun 2012;14(3):254-263.
    [12]Mahdavian Delavary B, van der Veer WM, van Egmond M, Niessen FB, Beelen RH. Macrophages in skin injury and repair. Immunobiology. Jul 2011;216(7):753-762.
    [13]Martin P, Leibovich SJ. Inflammatory cells during wound repair:the good, the bad and the ugly. Trends Cell Biol. Nov 2005;15(11):599-607.
    [14]Medina RJ, O'Neill CL, O'Doherty TM, et al. Myeloid angiogenic cells act as alternative M2 macrophages and modulate angiogenesis through interleukin-8. Mol Med. Sep-Oct 2011;17(9-10):1045-1055.
    [15]Xu W, Zhao X, Daha MR, van Kooten C. Reversible differentiation of pro-and anti-inflammatory macrophages. Mol Immunol. Mar 2013;53(3):179-186.
    [16]Shachar I, Karin N. The dual roles of inflammatory cytokines and chemokines in the regulation of autoimmune diseases and their clinical implications. JLeukoc Biol. Sep 4 2012.
    [17]van der Valk FM, van Wijk DF, Stroes ES. Novel anti-inflammatory strategies in atherosclerosis. Curr Opin Lipidol. Dec 2012;23(6):532-539.
    [18]Zimmermann HW, Trautwein C, Tacke F. Functional role of monocytes and macrophages for the inflammatory response in acute liver injury. Front Physiol.2012;3:56.
    [19]Koh TJ, DiPietro LA. Inflammation and wound healing:the role of the macrophage. Expert Rev Mol Med.2011;13:e23.
    [20]Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. Nov 2011;11(11):723-737.
    [21]Spencer M, Yao-Borengasser A, Unal R, et al. Adipose tissue macrophages in insulin-resistant subjects are associated with collagen VI and fibrosis and demonstrate alternative activation. Am J Physiol Endocrinol Metab. Dec 2010;299(6):E1016-1027.
    [22]Kanter JE, Kramer F, Barnhart S, et al. Diabetes promotes an inflammatory macrophage phenotype and atherosclerosis through acyl-CoA synthetase 1. Proc Natl Acad Sci U S A. Mar 20 2012;109(12):E715-724.
    [23]Mantovani A, Sica A, Locati M. New vistas on macrophage differentiation and activation. Eur J Immunol.Jan 2007;37(1):14-16.
    [24]Wall EA, Zavzavadjian JR., Chang MS, et al. Suppression of LPS-induced TNF-alpha production in macrophages by cAMP is mediated by PKA-AKAP95-p105. Sci Signal.2009;2(75):ra28.
    [25]Ma L, Dong F, Zaid M, Kumar A, Zha X. ABCA1 Protein Enhances Toll-like Receptor 4 (TLR4)-stimulated Interleukin-10 (IL-10) Secretion through Protein Kinase A (PKA) Activation. J Biol Chem. Nov 23 2012;287(48):40502-40512.
    [26]Hasturk H, Kantarci A, Van Dyke TE. Oral inflammatory diseases and systemic inflammation:role of the macrophage. Front Immunol.2012;3:118.
    [27]Edwards JP, Zhang X, Frauwirth KA, Mosser DM. Biochemical and functional characterization of three activated macrophage populations. JLeukoc Biol. Dec 2006;80(6):1298-1307.
    [28]Brys L, Beschin A, Raes G, et al. Reactive oxygen species and 12/15-lipoxygenase contribute to the antiproliferative capacity of alternatively activated myeloid cells elicited during helminth infection. J Immunol. May 15 2005;174(10):6095-6104.
    [29]Gerber JS, Mosser DM. Reversing lipopolysaccharide toxicity by ligating the macrophage Fc gamma receptors. J Immunol. Jun 1 2001;166(11):6861-6868.
    [30]Aderem A, Ulevitch RJ. Toll-like receptors in the induction of the innate immune response. Nature. Aug 17 2000;406(6797):782-787.
    [31]Newton K, Dixit VM. Signaling in innate immunity and inflammation. Cold Spring Harb Perspect Biol. Mar 2012;4(3).
    [32]Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling. Cell Death Differ. Jan 2003;10(1):45-65.
    [33]Graves D. Cytokines that promote periodontal tissue destruction. J Periodontol. Aug 2008;79(8 Suppl):1585-1591.
    [34]Sander AL, Henrich D, Muth CM, Marzi I, Barker JH, Frank JM. In vivo effect of hyperbaric oxygen on wound angiogenesis and epithelialization. Wound Repair Regen. Mar-Apr 2009; 17(2):179-184.
    [35]Siqueira MF, Li J, Chehab L, et al. Impaired wound healing in mouse models of diabetes is mediated by TNF-alpha dysregulation and associated with enhanced activation of forkhead box 01 (FOXO1). Diabetologia. Feb 2010;53(2):378-388.
    [36]Landis RC, Evans BJ, Chaturvedi N, Haskard DO. Persistence of TNFalpha in diabetic wounds. Diabetologia. Jul 2010;53(7):1537-1538.
    [37]Brunner G, Blakytny R. Extracellular regulation of TGF-beta activity in wound repair:growth factor latency as a sensor mechanism for injury. Thromb Haemost. Aug 2004;92(2):253-261.
    [38]Tandon A, Tovey JC, Sharma A, Gupta R, Mohan RR. Role of transforming growth factor Beta in corneal function, biology and pathology. Curr Mol Med. Aug 2010;10(6):565-578.
    [39]Bullard KM, Longaker MT, Lorenz HP. Fetal wound healing:current biology. World J Surg. Jan 2003;27(1):54-61.
    [40]Arnold L, Henry A, Poron F, et al. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J Exp Med. May 14 2007;204(5):1057-1069.
    [41]Deng B, Wehling-Henricks M, Villalta SA, Wang Y, Tidball JG. IL-10 triggers changes in macrophage phenotype that promote muscle growth and regeneration. J Immunol. Oct 12012;189(7):3669-3680.
    [42]Pinderski LJ, Fischbein MP, Subbanagounder G, et al. Overexpression of interleukin-10 by activated T lymphocytes inhibits atherosclerosis in LDL receptor-deficient Mice by altering lymphocyte and macrophage phenotypes. Circ Res. May 312002;90(10):1064-1071.
    [43]Seljeflot I, Hurlen M, Solheim S, Arnesen H. Serum levels of interleukin-10 are inversely related to future events in patients with acute myocardial infarction. J Thromb Haemost. Feb 2004;2(2):350-352.
    [44]Krishnamurthy P, Rajasingh J, Lambers E, Qin G, Losordo DW, Kishore R. IL-10 inhibits inflammation and attenuates left ventricular remodeling after myocardial infarction via activation of STAT3 and suppression of HuR. Circ Res. Jan 30 2009;104(2):e9-18.
    [45]Yang Z, Zingarelli B, Szabo C. Crucial role of endogenous interleukin-10 production in myocardial ischemia/reperfusion injury. Circulation. Mar 7 2000;101(9):1019-1026.
    [46]Esche C, Stellato C, Beck LA. Chemokines:key players in innate and adaptive immunity. J Invest Dermatol. Oct 2005;125(4):615-628.
    [47]Yumoto H, Nakae H, Fujinaka K, Ebisu S, Matsuo T. Interleukin-6 (IL-6) and IL-8 are induced in human oral epithelial cells in response to exposure to periodontopathic Eikenella corrodens. Infect Immun. Jan 1999;67(1):384-394.
    [48]Bendre MS, Montague DC, Peery T, Akel NS, Gaddy D, Suva LJ. Interleukin-8 stimulation of osteoclastogenesis and bone resorption is a mechanism for the increased osteolysis of metastatic bone disease. Bone. Jul 2003;33(1):28-37.
    [49]Koch AE, Polverini PJ, Kunkel SL, et al. Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science. Dec 11 1992;258(5089):1798-1801.
    [50]Okamatsu Y, Kim D, Battaglino R, Sasaki H, Spate U, Stashenko P. MIP-1 gamma promotes receptor-activator-of-NF-kappa-B-ligand-induced osteoclast formation and survival. J Immunol. Aug 1 2004;173(3):2084-2090.
    [51]Thorp EB. Contrasting Inflammation Resolution during Atherosclerosis and Post Myocardial Infarction at the Level of Monocyte/Macrophage Phagocytic Clearance. Front Immunol.2012;3:39.
    [52]Dewald O, Zymek P, Winkelmann K, et al. CCL2/Monocyte Chemoattractant Protein-1 regulates inflammatory responses critical to healing myocardial infarcts. Circ Res. Apr 29 2005;96(8):881-889.
    [53]Panizzi P, Swirski FK, Figueiredo JL, et al. Impaired infarct healing in atherosclerotic mice with Ly-6C(hi) monocytosis. J Am Coll Cardiol. Apr 13 2010;55(15):1629-1638.
    [54]McColl A, Michlewska S, Dransfield I, Rossi AG. Effects of glucocorticoids on apoptosis and clearance of apoptotic cells. ScientificWorldJournal.2007;7:1165-1181.
    [55]Galon J, Franchimont D, Hiroi N, et al. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J. Jan 2002;16(1):61-71.
    [1]Norrving B, Kissela B. The global burden of stroke and need for a continuum of care. Neurology. Jan 15 2013;80(3 Suppl 2):S5-12.
    [2]范惠珍.青年缺血性脑卒中的病因分析及危险因素预后分析.中国医药指南.2012；10(27)：474-475.
    [3]Strazzullo P, D'Elia L, Cairella G, Garbagnati F, Cappuccio FP, Scalfi L. Excess body weight and incidence of stroke:meta-analysis of prospective studies with 2 million participants. Stroke. May 2010;41(5):e418-426.
    [4]王陇德.中国居民营养与健康状况调查报告之一 2002 综合报告人民卫生出版社；2005.
    [5]Whitlock G, Lewington S, Sherliker P, et al. Body-mass index and cause-specific mortality in 900 000 adults:collaborative analyses of 57 prospective studies. Lancet. Mar 28 2009;373(9669):1083-1096.
    [6]Gu D, He J, Duan X, et al. Body weight and mortality among men and women in China. JAMA. Feb 15 2006;295(7):776-783.
    [7]Flegal KM, Graubard BI, Williamson DF, Gail MH. Cause-specific excess deaths associated with underweight, overweight, and obesity. JAMA. Nov 7 2007;298(17):2028-2037.
    [8]Berrington de Gonzalez A, Hartge P, Cerhan JR, et al. Body-mass index and mortality among 1.46 million white adults. NEngl J Med. Dec 2 2010;363(23):2211-2219.
    [9]Oreopoulos A, Padwal R, Kalantar-Zadeh K, Fonarow GC, Norris CM, McAlister FA. Body mass index and mortality in heart failure:a meta-analysis. Am Heart J. Jul 2008;156(1):13-22.
    [10]Romero-Corral A, Montori VM, Somers VK, et al. Association of bodyweight with total mortality and with cardiovascular events in coronary artery disease:a systematic review of cohort studies. Lancet. Aug 19 2006;368(9536):666-678.
    [11]Lavie CJ, Osman AF, Milani RV, Mehra MR. Body composition and prognosis in chronic systolic heart failure:the obesity paradox. Am J Cardiol. Apr 12003;91(7):891-894.
    [12]Ferreira I, Stehouwer CD. Obesity paradox or inappropriate study designs? Time for life-course epidemiology. JHypertens. Dec 2012;30(12):2271-2275.
    [13]Kenchaiah S, Evans JC, Levy D, et al. Obesity and the risk of heart failure. N Engl J Med. Aug 1 2002;347(5):305-313.
    [14]Alpert MA, Terry BE, Mulekar M, et al. Cardiac morphology and left ventricular function in normotensive morbidly obese patients with and without congestive heart failure, and effect of weight loss. Am J Cardiol. Sep 15 1997;80(6):736-740.
    [15]Alpert MA. Obesity cardiomyopathy:pathophysiology and evolution of the clinical syndrome. Am J Med Sci. Apr 2001;321(4):225-236.
    [16]Lavie CJ, Milani RV, Ventura HO, Cardenas GA, Mehra MR, Messerli FH. Disparate effects of left ventricular geometry and obesity on mortality in patients with preserved left ventricular ejection fraction. Am J Cardiol. Nov 1 2007;100(9):1460-1464.
    [17]Wang TJ, Parise H, Levy D, et al. Obesity and the risk of new-onset atrial fibrillation. JAMA, Nov 24 2004;292(20):2471-2477.
    [18]Fonarow GC, Srikanthan P, Costanzo MR, Cintron GB, Lopatin M. An obesity paradox in acute heart failure:analysis of body mass index and inhospital mortality for 108,927 patients in the Acute Decompensated Heart Failure National Registry. Am Heart J. Jan 2007;153(1):74-81.
    [19]Tsai PS, Ke TL, Huang CJ, et al. Prevalence and determinants of prehypertension status in the Taiwanese general population. JHypertens. Jul 2005;23(7):1355-1360.
    [20]Uretsky S, Messerli FH, Bangalore S, et al. Obesity paradox in patients with hypertension and coronary artery disease. Am JMed. Oct 2007;120(10):863-870.
    [21]Madala MC, Franklin BA, Chen AY, et al. Obesity and age of first non-ST-segment elevation myocardial infarction. J Am Coll Cardiol. Sep 16 2008;52(12):979-985.
    [22]Romero-Corral A, Sierra-Johnson J, Lopez-Jimenez F, et al. Relationships between leptin and C-reactive protein with cardiovascular disease in the adult general population. Nat Clin Pract Cardiovasc Med. Jul 2008;5(7):418-425.
    [23]Kosuge M, Kimura K, Kojima S, et al. Impact of body mass index on in-hospital outcomes after percutaneous coronary intervention for ST segment elevation acute myocardial infarction. Circ J. Apr 2008;72(4):521-525.
    [24]Thompson J. Management of obesity in Scotland:development of the latest evidence-based recommendations. Proc Nutr Soc. May 2010;69(2):195-198.
    [25]Kim BJ, Lee SH, Ryu WS, Kim CK, Lee J, Yoon BW. Paradoxical longevity in obese patients with intracerebral hemorrhage. Neurology. Feb 8 2011;76(6):567-573.
    [26]Ovbiagele B, Bath PM, Cotton D, Vinisko R, Diener HC. Obesity and recurrent vascular risk after a recent ischemic stroke. Stroke. Dec 2011;42(12):3397-3402.
    [27]Vemmos K, Ntaios G, Spengos K, et al. Association between obesity and mortality after acute first-ever stroke:the obesity-stroke paradox. Stroke. Jan 2011;42(1):30-36.
    [28]Towfighi A, Ovbiagele B. The impact of body mass index on mortality after stroke. Stroke. Aug 2009;40(8):2704-2708.
    [29]Kim BJ, Lee SH, Jung KH, Yu KH, Lee BC, Roh JK. Dynamics of obesity paradox after stroke, related to time from onset, age, and causes of death. Neurology. Aug 28 2012;79(9):856-863.
    [30]Sheffler LR, Knutson JS, Gunzler D, Chae J. Relationship between body mass index and rehabilitation outcomes in chronic stroke. Am J Phys Med Rehabil. Nov 2012;91(11):951-956.
    [31]Scherbakov N, Dirnagl U, Doehner W. Body weight after stroke:lessons from the obesity paradox. Stroke. Dec 2011;42(12):3646-3650.
    [32]Tan CE, Ma S, Wai D, Chew SK, Tai ES. Can we apply the National Cholesterol Education Program Adult Treatment Panel definition of the metabolic syndrome to Asians? Diabetes Care. May 2004;27(5):1182-1186.
    [33]Litwin SE. Which measures of obesity best predict cardiovascular risk? J Am Coll Cardiol. Aug 19 2008;52(8):616-619.
    [34]Pischon T, Boeing H, Hoffmann K, et al. General and abdominal adiposity and risk of death in Europe. NEngl J Med. Nov 13 2008;359(20):2105-2120.
    [35]Sun L, Li Z, Zhang H, et al. Pentanucleotide TTTTA repeat polymorphism of apolipoprotein(a) gene and plasma lipoprotein(a) are associated with ischemic and hemorrhagic stroke in Chinese:a multicenter case-control study in China. Stroke. Jul 2003;34(7):1617-1622.
    [36]Larsson B, Svardsudd K, Welin L, Wilhelmsen L, Bjorntorp P, Tibblin G. Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death:13 year follow up of participants in the study of men born in 1913. Br Med J (Clin Res Ed). May 12 1984;288(6428):1401-1404.
    [37]Dixon JB. The effect of obesity on health outcomes. Mol Cell Endocrinol. Mar 25 2010;316(2):104-108.
    [38]He J, Gu D, Wu X, et al. Major causes of death among men and women in China. N Engl J Med. Sep 152005;353(11):1124-1134.
    [39]Deurenberg-Yap M, Schmidt G, van Staveren WA, Deurenberg P. The paradox of low body mass index and high body fat percentage among Chinese, Malays and Indians in Singapore. Int J Obes RelatMetab Disord. Aug 2000;24(8):1011-1017.
    [40]Wu CH, Heshka S, Wang J, et al. Truncal fat in relation to total body fat:influences of age, sex, ethnicity and fatness. Int J Obes (Lond). Sep 2007;31(9):1384-1391.
    [41]Nicklas BJ, Penninx BW, Cesari M, et al. Association of visceral adipose tissue with incident myocardial infarction in older men and women:the Health, Aging and Body Composition Study. Am J Epidemiol. Oct 15 2004;160(8):741-749.
    [42]Kuk JL, Katzmarzyk PT, Nichaman MZ, Church TS, Blair SN, Ross R. Visceral fat is an independent predictor of all-cause mortality in men. Obesity (Silver Spring). Feb 2006;14(2):336-341.
    [43]Yusuf S, Hawken S, Ounpuu S, et al. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries:a case-control study. Lancet. Nov 5 2005;366(9497):1640-1649.
    [44]Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. May 16 2001;285(19):2486-2497.
    [45]Shao J, Yu L, Shen X, Li D, Wang K. Waist-to-height ratio, an optimal predictor for obesity and metabolic syndrome in Chinese adults. J Nutr Health Aging. Nov 2010;14(9):782-785.
    [46]de Koning L, Merchant AT, Pogue J, Anand SS. Waist circumference and waist-to-hip ratio as predictors of cardiovascular events:meta-regression analysis of prospective studies. Eur Heart J. Apr 2007;28(7):850-856.
    [47]van Dis I, Kromhout D, Geleijnse JM, Boer JM, Verschuren WM. Body mass index and waist circumference predict both 10-year nonfatal and fatal cardiovascular disease risk:study conducted in 20,000 Dutch men and women aged 20-65 years. Eur J Cardiovasc Prev Rehabil. Dec 2009;16(6):729-734.
    [48]Taylor AE, Ebrahim S, Ben-Shlomo Y, et al. Comparison of the associations of body mass index and measures of central adiposity and fat mass with coronary heart disease, diabetes, and all-cause mortality:a study using data from 4 UK cohorts. Am J Clin Nutr. Mar 2010;91(3):547-556.
    [49]Zhang C, Rexrode KM, van Dam RM, Li TY, Hu FB. Abdominal obesity and the risk of all-cause, cardiovascular, and cancer mortality:sixteen years of follow-up in US women. Circulation. Apr 1 2008;117(13):1658-1667.
    [50]Czernichow S, Kengne AP, Stamatakis E, Hamer M, Batty GD. Body mass index, waist circumference and waist-hip ratio:which is the better discriminator of cardiovascular disease mortality risk?: evidence from an individual-participant meta-analysis of 82 864 participants from nine cohort studies. Obes Rev. Sep 2011;12(9):680-687.
    [51]Gielen S, Sandri M. The obesity paradox-A scientific artifact? Int J Cardiol. Jan 20 2013;162(3):140-142.
    [52]Perk J, De Backer G, Gohlke H, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. Jul 2012;33(13):1635-1701.
    [53]Smith SC, Jr., Benjamin EJ, Bonow RO, et al. AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease:2011 update:a guideline from the American Heart Association and American College of Cardiology Foundation. Circulation. Nov 29 2011;124(22):2458-2473.
    [54]Dixon JB, Lambert GW. The obesity paradox-A reality that requires explanation and clinical interpretation. Atherosclerosis. Jan 2013;226(1):47-48.
    [55]Oreopoulos A, Kalantar-Zadeh K, Sharma AM, Fonarow GC. The obesity paradox in the elderly: potential mechanisms and clinical implications. Clin Geriatr Med. Nov 2009;25(4):643-659, viii.
    [56]Imbeault P, Tremblay A, Simoneau JA, Joanisse DR. Weight loss-induced rise in plasma pollutant is associated with reduced skeletal muscle oxidative capacity. Am J Physiol Endocrinol Metab. Mar 2002;282(3):E574-579.
    [57]Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. Jun 2004;89(6):2548-2556.
    [58]Schulze PC, Kratzsch J, Linke A, et al. Elevated serum levels of leptin and soluble leptin receptor in patients with advanced chronic heart failure. Eur J Heart Fail. Jan 2003;5(1):33-40.
    [59]Takeishi Y, Niizeki T, Arimoto T, et al. Serum resistin is associated with high risk in patients with congestive heart failure--a novel link between metabolic signals and heart failure. Circ J. Apr 2007;71(4):460-464.
    [60]Kim M, Oh JK, Sakata S, et al. Role of resistin in cardiac contractility and hypertrophy. J Mol Cell Cardiol. Aug 2008;45(2):270-280.
    [61]Shamsuzzaman AS, Winnicki M, Wolk R, et al. Independent association between plasma leptin and C-reactive protein in healthy humans. Circulation. May 11 2004;109(18):2181-2185.
    [62]Havel PJ. Update on adipocyte hormones:regulation of energy balance and carbohydrate/lipid metabolism. Diabetes. Feb 2004;53 Suppl 1:S143-151.
    [63]Castan-Laurell I, Dray C, Knauf C, Kunduzova O, Valet P. Apelin, a promising target for type 2 diabetes treatment? Trends Endocrinol Metab. May 2012;23(5):234-241.
    [64]Lee DK, George SR, O'Dowd BF. Unravelling the roles of the apelin system:prospective therapeutic applications in heart failure and obesity. Trends Pharmacol Sci. Apr 2006;27(4):190-194.
    [65]Japp AG, Newby DE. The apelin-APJ system in heart failure:pathophysiologic relevance and therapeutic potential. Biochem Pharmacol. May 15 2008;75(10):1882-1892.
    [66]Feldman AM, Combes A, Wagner D, et al. The role of tumor necrosis factor in the pathophysiology of heart failure. J Am Coll Cardiol. Mar 12000;35(3):537-544.
    [67]Esler M, Kaye D. Sympathetic nervous system activation in essential hypertension, cardiac failure and psychosomatic heart disease. J CardiovascPharmacol.2000;35(7 Suppl 4):S1-7.
    [68]Hong NS, Kim KS, Lee IK, et al. The association between obesity and mortality in the elderly differs by serum concentrations of persistent organic pollutants:a possible explanation for the obesity paradox. Int J Obes (Lond). Sep 2012;36(9):1170-1175.
    [69]Neels JG, Olefsky JM. Inflamed fat:what starts the fire? J Clin Invest. Jan 2006;116(1):33-35.
    [70]Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW, Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. Dec 2003; 112(12):1796-1808.
    [71]Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. Jan 2007;117(1):175-184.
    [72]Coenen KR, Gruen ML, Chait A, Hasty AH. Diet-induced increases in adiposity, but not plasma lipids, promote macrophage infiltration into white adipose tissue. Diabetes. Mar 2007;56(3):564-573.
    [73]Weisberg SP, Hunter D, Huber R, et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. JClin Invest. Jan 2006;116(1):115-124.
    [74]Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. Nov 2006;116(11):3015-3025.
    [75]Boden G, She P, Mozzoli M, et al. Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-kappaB pathway in rat liver. Diabetes. Dec 2005;54(12):3458-3465.
    [76]Yu C, Chen Y, Cline GW, et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem. Dec 27 2002;277(52):50230-50236.
    [77]Galic S, Oakhill JS, Steinberg GR. Adipose tissue as an endocrine organ. Mol Cell Endocrinol. Mar 25 2010;316(2):129-139.
    [1]C. P. Ponting and T. G. Belgard, "Transcribed dark matter:meaning or myth?," Human Molecular Genetics, vol.19, pp. R162-R168, October 15,2010 2010.
    [2]M. Guttman, I. Amit, M. Garber, C. French, M. F. Lin, D. Feldser, et al., "Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals," Nature, vol.458, pp.223-227,03/12/print 2009.
    [3]S. C. Wu, E. M. Kallin, and Y. Zhang, "Role of H3K27 methylation in the regulation of LncRNA expression," Cell Res, vol.20, pp.1109-1116,10//print 2010.
    [4]L. Lipovich, R. Johnson, and C.-Y. Lin, "MacroRNA underdogs in a microRNA world: Evolutionary, regulatory, and biomedical significance of mammalian long non-protein-coding RNA," Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms, vol.1799, pp. 597-615,9//2010.
    [5]T. Kondo, S. Plaza, J. Zanet, E. Benrabah, P. Valenti, Y. Hashimoto, et al, "Small peptides switch the transcriptional activity of Shavenbaby during Drosophila embryogenesis," Science (New York, N.Y.), vol.329, pp.336-339,07/2010.
    [6]U. A.(?)rom, T. Derrien, M. Beringer, K. Gumireddy, A. Gardini, G. Bussotti, et al., "Long Noncoding RNAs with Enhancer-like Function in Human Cells," Cell, vol.143, pp.46-58,10/1/ 2010.
    [7]C. P. Ponting, P. L. Oliver, and W. Reik, "Evolution and Functions of Long Noncoding RNAs," Cell, vol.136, pp.629-641,2/20/2009.
    [8]M. Lapidot and Y. Pilpel, "Genome-wide natural antisense transcription:coupling its regulation to its different regulatory mechanisms," EMBO Rep, vol.7, pp.1216-22, Dec 2006.
    [9]R. Louro, T. El-Jundi, H. I. Nakaya, E. M. Reis, and S. Verjovski-Almeida, "Conserved tissue expression signatures of intronic noncoding RNAs transcribed from human and mouse loci," Genomics, vol.92, pp.18-25, Jul 2008.
    [10]T. R. Mercer, M. E. Dinger, S. M. Sunkin, M. F. Mehler, and J. S. Mattick, "Specific expression of long noncoding RNAs in the mouse brain," Proc Natl Acad Sci U S A, vol.105, pp.716-21, Jan 15 2008.
    [11]J. Ponjavic, C. P. Ponting, and G. Lunter, "Functionality or transcriptional noise? Evidence for selection within long noncoding RNAs," Genome Res, vol.17, pp.556-65, May 2007.
    [12]T. Ravasi, H. Suzuki, K. C. Pang, S. Katayama, M. Furuno, R. Okunishi, et al., "Experimental validation of the regulated expression of large numbers of non-coding RNAs from the mouse genome," Genome Res, vol.16, pp.11-9, Jan 2006.
    [13]V. Tripathi, J. D. Ellis, Z. Shen, D. Y. Song, Q. Pan, A. T. Watt, et al., "The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation," Mol Cell, vol.39, pp.925-38, Sep 24 2010.
    [14]Y. Ogawa, B. K. Sun, and J. T. Lee, "Intersection of the RNA interference and X-inactivation pathways," Science, vol.320, pp.1336-41, Jun 6 2008.
    [15]C. Gregg, J. Zhang, B. Weissbourd, S. Luo, G. P. Schroth, D. Haig, et al., "High-resolution analysis of parent-of-origin allelic expression in the mouse brain," Science, vol.329, pp.643-8, Aug 6 2010.
    [16]T. Nagano, J. A. Mitchell, L. A. Sanz, F. M. Pauler, A. C. Ferguson-Smith, R. Feil, et al., "The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin," Science, vol. 322, pp.1717-20, Dec 12 2008.
    [17]R. R. Pandey, T. Mondal, F. Mohammad, S. Enroth, L. Redrup, J. Komorowski, et al., "Kcnqlotl antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation," Mol Cell, vol.32, pp.232-46, Oct 24 2008.
    [18]J. Zhao, T. K. Ohsumi, J. T. Kung, Y. Ogawa, D. J. Grau, K. Sarma, et al., "Genome-wide identification of polycomb-associated RNAs by RIP-seq," Mol Cell, vol.40, pp.939-53, Dec 22 2010.
    [19]M. E. Dinger, P. P. Amaral, T. R. Mercer, K. C. Pang, S. J. Bruce, B. B. Gardiner, et al., "Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation," Genome Res, vol.18, pp.1433-45, Sep 2008.
    [20]T. R. Mercer, I. A. Qureshi, S. Gokhan, M. E. Dinger, G. Li, J. S. Mattick, et al., "Long noncoding RNAs in neuronal-glial fate specification and oligodendrocyte lineage maturation," BMC Neurosci, vol.11, p.14,2010.
    [21]K. C. Pang, M. E. Dinger, T. R. Mercer, L. Malquori, S. M. Grimmond, W. Chen, et al., "Genome-wide identification of long noncoding RNAs in CD8+T cells," J Immunol, vol.182, pp. 7738-48, Jun 15 2009.
    [22]S. Loewer, M. N. Cabili, M. Guttman, Y. H. Loh, K. Thomas, I. H. Park, et al., "Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells," Nat Genet, vol.42, pp.1113-7, Dec 2010.
    [23]P. Navarro, I. Chambers, V. Karwacki-Neisius, C. Chureau, C. Morey, C. Rougeulle, et al., "Molecular coupling of Xist regulation and pluripotency," Science, vol.321, pp.1693-5, Sep 19 2008.
    [24]M. E. Donohoe, S. S. Silva, S. F. Pinter, N. Xu, and J. T. Lee, "The pluripotency factor Oct4 interacts with Ctcf and also controls X-chromosome pairing and counting," Nature, vol.460, pp. 128-32, Jul 2 2009.
    [25]T. Kino, D. E. Hurt, T. Ichijo, N. Nader, and G. P. Chrousos, "Noncoding RNA gas5 is a growth arrest-and starvation-associated repressor of the glucocorticoid receptor," Sci Signal, vol.3, p. ra8, 2010.
    [26]C. S. Bond and A. H. Fox, "Paraspeckles:nuclear bodies built on long noncoding RNA," J Cell Biol, vol.186, pp.637-44, Sep 7 2009.
    [27]J. L. Rinn, M. Kertesz, J. K. Wang, S. L. Squazzo, X. Xu, S. A. Brugmann, et al., "Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs," Cell, vol.129, pp.1311-23, Jun 29 2007.
    [28]T. K. Kim, M. Hemberg, J. M. Gray, A. M. Costa, D. M. Bear, J. Wu, et al., "Widespread transcription at neuronal activity-regulated enhancers," Nature, vol.465, pp.182-7, May 13 2010.
    [29]U. A. Orom, T. Derrien, M. Beringer, K. Gumireddy, A. Gardini, G. Bussotti, et al., "Long noncoding RNAs with enhancer-like function in human cells," Cell, vol.143, pp.46-58, Oct 1 2010.
    [30]N. Ishii, K. Ozaki, H. Sato, H. Mizuno, S. Susumu, A. Takahashi, et al., "Identification of a novel non-coding RNA, MIAT, that confers risk of myocardial infarction," Journal of Human Genetics, vol.51, pp.1087-1099,2006/12/012006.
    [31]R. McPherson, A. Pertsemlidis, N. Kavaslar, A. Stewart, R. Roberts, D. R. Cox, et al., "A common allele on chromosome 9 associated with coronary heart disease," Science (New York, N. Y), vol. 316, pp.1488-1491,06/2007.
    [32]H. M. Broadbent, J. F. Peden, S. Lorkowski, A. Goel, H. Ongen, F. Green, et al, "Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p," Human Molecular Genetics, vol.17, pp.806-814, March 15,2008 2008.
    [33]M. C. Puri, J. Partanen, J. Rossant, and A. Bernstein, "Interaction of the TEK and TIE receptor tyrosine kinases during cardiovascular development," Development (Cambridge, England), vol. 126, pp.4569-4580,10/1999.
    [34]K. Li, Y. Blum, A. Verma, Z. Liu, K. Pramanik, N. R. Leigh, et al., "A noncoding antisense RNA in tie-1 locus regulates tie-1 function in vivo," Blood, vol.115, pp.133-139,01/2010.
    [35]N. R. Madamanchi, Z. Y. Hu, F. Li, C. Horaist, S. K. Moon, C. Patterson, et al., "A noncoding RNA regulates human protease-activated receptor-1 gene during embryogenesis," Biochimica et biophysica acta, vol.1576, pp.237-245,07/2002.
    [36]C. E. Burd, W. R. Jeck, Y. Liu, H. K. Sanoff, Z. Wang, and N. E. Sharpless, "Expression of Linear and Novel Circular Forms of anINK4/ARF-Associated Non-Coding RNA Correlates with Atherosclerosis Risk," PLoS Genet, vol.6, p. e1001233,2010.
    [37]O. Jarinova, A. F. R. Stewart, R. Roberts, G. Wells, P. Lau, T. Naing, et al, "Functional Analysis of the Chromosome 9p21.3 Coronary Artery Disease Risk Locus," Arteriosclerosis, Thrombosis, and Vascular Biology, July 10,2009 2009.
    [38]R. T. Brookheart, C. I. Michel, L. L. Listenberger, D. S. Ory, and J. E. Schaffer, "The Non-coding RNA gadd7 Is a Regulator of Lipid-induced Oxidative and Endoplasmic Reticulum Stress," Journal of Biological Chemistry, vol.284, pp.7446-7454, March 20,2009 2009.
    [39]J. Giger, A. X. Qin, P. W. Bodell, K. M. Baldwin, and F. Haddad, "Activity of the β-myosin heavy chain antisense promoter responds to diabetes and hypothyroidism," American Journal of Physiology-Heart and Circulatory Physiology, vol.292, pp. H3065-H3071, June 1,2007 2007.
    [40]F. Haddad, A. X. Qin, P. W. Bodell, L. Y. Zhang, H. Guo, J. M. Giger, et al, "Regulation of antisense RNA expression during cardiac MHC gene switching in response to pressure overload," American Journal of Physiology-Heart and Circulatory Physiology, vol.290, pp. H2351-H2361, June 1,2006 2006.
    [41]J. Zhao, J. Sinclair, J. Houghton, E. Bolton, A. Bradley, and A. Lever, "Cytomegalovirus beta2.7 RNA transcript protects endothelial cells against apoptosis during ischemia/reperfusion injury," J Heart Lung Transplant, vol.29, pp.342-5, Mar 2010.