摘要
研究背景
左室肥厚是高血压最常见的靶器官损害之一。而左室肥厚最终可进展至心功能不全和/或心力衰竭(HF)。在高血压的早期即可出现左室舒张功能障碍,且发生在收缩功能受损之前。但高血压左室肥厚致左室舒张功能障碍的发生机制目前尚未完全阐明。研究发现,高血压主要靶器官(心、脑、肾)中均存在细胞凋亡现象,而且心肌细胞的凋亡和心肌肥厚、心功能障碍均密切相关。因此认为,大量心肌细胞的凋亡可能是促使心肌肥厚走向心功能障碍的重要原因。
内质网应激(endoplasmic reticulum stress,ERS)是内质网功能紊乱时出现错误折叠与未折叠蛋白在腔内聚集以及Ca~(2+)平衡紊乱的状态。多种生理或病理条件,如分泌细胞过度分泌、分泌性蛋白基因突变、化学物质致内质网损伤等均可引起ERS。目前已经明确的ERS介导的凋亡通路有三条:①CHOP/GADD153(growtharrest and DNA damage-inducible gene 153)基因的激活转录;②JNK(c-JunNH2-terminal protein kinase)的激活通路;③内质网特有的半胱氨酸蛋白酶Caspase-12的激活通路。
经研究发现ERS作为一条应激通路,参与了多种疾病的发生,同时也发现ERS参与介导心肌细胞的凋亡。作为应激状态下普遍存在的一种亚细胞器病理过程,ERS是否也在高血压诱导的左室肥厚致左室舒张功能障碍的过程中发挥作用目前仍尚不清楚。
全身及心肌局部肾素-血管紧张素系统(RAS)的激活是高血压重要的病理生理改变。血管紧张素Ⅱ(AngⅡ)是RAS系统中最重要的效应分子。越来越多的实验证实,AngⅡ是促使心肌细胞凋亡的重要诱因之一。AngⅡ受体拮抗剂是高血压,特别是高血压伴左室肥厚患者的一线药物。但该类药物改善左室重构是否与参与调节ERS有关尚未明确。
本研究希望能为高血压的左室重构在亚细胞器和分子水平引入新的概念和理论,并为左室肥厚以及左室舒张功能障碍的预防和治疗提供新的靶点。
研究目的
(1)验证高血压左室肥厚致左室舒张功能障碍过程中存在细胞凋亡的增加,明确凋亡在高血压致心肌功能障碍过程中发挥的作用。
(2)明确高血压左室肥厚致左室舒张功能障碍过程中是否存在ERS的激活。
(3)明确高血压左室肥厚致左室舒张功能障碍过程中是通过哪条或哪几条与ERS相关的途径介导心肌细胞凋亡。
(4)明确AT1受体拮抗剂是否通过参与调节ERS发挥逆转左室肥厚、延缓心衰的出现和发展的作用。
研究方法
1动物模型构建
1.1高血压所致左室肥厚以及左室舒张功能障碍模型的建立
购买普通Wistar-Kyoto(WKY)大鼠(8周龄)30只和自发性高血压大鼠(SHRs)(8周龄)30只。随机各取10只8周龄SHRs和10只WKY大鼠处死后保留心脏标本,余给予普通饲料分别喂养至16周、32周。应用超声心动图等技术判定各组大鼠左室肥厚程度以及左室舒张功能。大鼠符合实验要求后全部处死,留取标本。
1.2缬沙坦的干预实验
选用SHRs和WKY大鼠为研究对象。购买普通WKY大鼠(16周龄)10只和SHRs(16周龄)20只。随机选取10只SHRs大鼠,给予缬沙坦进行药物干预(20mg/kg/d),其余大鼠均给予等量生理盐水,1次/d。所有大鼠均普食喂养至32周,全部处死后留取标本。
2大鼠收缩压的测定
大鼠40℃预热5-10分钟,采用RBP-1型大鼠无创尾动脉血压测定分析系统,测量大鼠安静、清醒状态下尾动脉收缩压和心率,连测三次,取其平均值。
3大鼠左室重量指数(left ventricular mass index,LVMI)的比较
LVMI=左心室重量(LVM,mg/体重(BM,g)。用分析天平称取LVM(包括室间隔),计算LVMI。
4超声心动图检测
分别于高血压左室肥厚、左室舒张功能障碍建模前以及建模后进行常规超声心动图检查。测定如下指标:室间隔(Interventricular septum,IVS)和左室后壁(LVPosterior wall,LVPW)厚度:左室射血分数(left ventricular ejective fraction,LVEF);左室短轴缩短率(fractional shortening,FS);二尖瓣E波最大速度、A波最大速度、E/A比值和等容舒张时间(Isovolumic relaxation time,IVRT)并观察瓣膜返流情况。
5心肌组织病理学检查
大鼠处死后,进行组织取材、固定、脱水、透明、浸蜡、石蜡包埋、切片,常规HE染色,观察心肌细胞形态并拍片。
6 TUNEL染色法鉴定凋亡细胞
取组织切片,进行TUNEL染色,观察细胞凋亡水平。
7免疫组织化学检测
取组织切片,进行GRP78、CHOP、p-JNK、Caspase-12、Caspase-3的免疫组织化学检测。所用一抗分别为:GRP78多克隆抗体(SantaCruz公司,1:200稀释);CHOP多克隆抗体(SantaCruz公司,1:200稀释);p-JNK多克隆抗体(SantaCruz公司,1:300稀释);Caspase-12多克隆抗体(SantaCruz公司,1:100稀释);Caspase-3多克隆抗体(SantaCruz公司,1:150稀释)。
8免疫印迹检测
取左室组织,提取总蛋白,经过SDS-聚丙烯酰胺凝胶电泳(SDS-PAGE)分离、转膜、蛋白印记、ECL显色等步骤,检测GRP78、CHOP、p-JNK、JNK、Caspase-12、Caspase-3的蛋白表达。
9 real time RT-PCR法检测
分别从左室组织提取总RNA,经逆转录反应(RT)得到cDNA,以GAPDH作为参照,通过real time RT-PCR技术检测GRP78、CHOP、p-JNK、Caspase-12 mRNA的表达。
研究结果
1实验动物基本情况及血压检测
(1)最终全部大鼠完成了实验。SHRs血压呈持续升高趋势。与同周龄的WKY大鼠相比,8周龄、16周龄、32周龄组SHRs的血压均显著升高(P＜0.05)。
(2)32周龄缬沙坦干预组大鼠较32周龄组SHRs血压显著降低(P＜0.05),与32周龄组WKY大鼠相较无显著性差异。
2左室重量指数(left ventricular mass index.LVMI)的比较
(1)与同周龄的WKY大鼠相比,8周龄组SHRs的LVMI未见明显变化;16周龄、32周龄组SHRs的LVMI均显著增加(P＜0.05)。与8周龄组SHRs相比,16周龄、32周龄组SHRs的LVMI均显著增加(P＜0.05,P＜0.01)。
(2)32周龄缬沙坦干预组大鼠较32周龄组SHRs的LVMI显著降低(P＜0.05)。
3超声心动图检测
(1)选用IVS和LVPW评价大鼠的左室肥厚程度;E/A比值、IVRT评价大鼠左室舒张功能;EF、FS评价大鼠左室收缩功能。与同周龄的WKY大鼠相比,16周龄和32周龄组SHRs的IVS和LVPW均明显增加(P＜0.05):16周龄组SHRs的IVRT明显延长(P＜0.05),E/A比值明显降低(P＜0.05);32周龄组SHRs的E/A比值显著增加(E/A＞＞2),出现左室舒张功能障碍的E/A比值变化趋势:早期降低,晚期升高,提示32周龄组的SHRs大鼠的心脏舒张功能己明显受损。EF以及FS在各组大鼠间均无显著性差异。
(2)同样选用上述指标评价表明:缬沙坦干预组大鼠较同周龄的SHRs相比,IVS和LVPW,E/A比值以及IVRT均显著降低(P＜0.05);EF以及FS在两组间均无显著性差异。
4光镜标本观察(HE染色)
(1)HE染色显示,对照组大鼠心肌细胞排列整齐,细胞核大小均一,胞浆染色均匀;8周龄组SHRs与对照组比较未见显著性变化,仍可见心肌细胞排列整齐,细胞核大小均一,胞浆染色均匀;16周龄组SHRs心肌细胞肥大,细胞核出现增大、畸形等改变,肌纤维排列较紊乱;32周龄组SHRs可出现心肌细胞的变性,呈局灶性、片状坏死,心肌纤维粗大、断裂等。微血管管壁增厚,官腔狭小,管周纤维组织增多。
(2)较32周龄组SHRs相比,32周龄缬沙坦干预组大鼠心肌细胞肥大,轻度变性,心肌纤维无断裂,心肌细胞核形状略不整,微血管管壁、管腔均正常,肌纤维排列较整齐。
5 TUNEL染色
(1)与同周龄的WKY大鼠相比,8周龄组SHRs的心肌细胞凋亡无明显增加;16周龄组SHRs的心肌细胞凋亡明显增加(P＜0.05);32周龄组SHRs的心肌细胞凋亡显著增加(P＜0.01)。与8周龄组的SHRs相比,16周龄、32周龄组SHRs心肌细胞凋亡均显著增加(P＜0.05,P＜0.01)。
(2)较32周龄组SHRs相比,32周龄缬沙坦干预组大鼠心肌细胞凋亡率明显降低(P＜0.05)。
6免疫组织化学检测
(1)GRP78、CHOP、Caspase-12、Caspase-3蛋白均定位于心肌细胞胞浆内,呈浅棕色颗粒。与同周龄的WKY大鼠相比,各组SHRs心肌细胞胞浆内GRP78、CHOP蛋白的表达均显著增加(P＜0.05);Caspase-12、Caspase-3蛋白只在16周龄和32周龄组SHRs心肌细胞胞浆内的表达显著增加(P＜0.05);p-JNK蛋白的表达在各组间未见明显差异。
(2)较32周龄组SHRs相比,缬沙坦干预组大鼠心肌细胞胞浆内的GRP78、CHOP、Caspase-3蛋白表达均显著减少(P＜0.05);p-JNK和Caspase-12蛋白表达未见明显变化。
7免疫印迹检测
(1)与同周龄的WKY大鼠相比,各组SHRs心肌组织的GRP78、CHOP蛋白表达均显著增加(P＜0.05,P＜0.01);Caspase-12和Caspase-3蛋白只在16周龄和32周龄组SHRs心肌组织中表达增多(P＜0.05,P＜0.01);JNK和p-JNK的蛋白表达各组间均无显著差异。
(2)较32周龄组SHRs相比,32周龄缬沙坦干预组大鼠心肌组织蛋白GRP78、CHOP的蛋白表达显著减少(P＜0.05)。Caspase-12的蛋白表达两组间未见明显变化。
8 real time RT-PCR法检测
(1)与同周龄的WKY大鼠相比,各组SHRs心肌组织的GRP78、CHOP mRNA表达均显著增加(P＜0.05,P＜0.01);Caspase-12 mRNA表达只在16周龄和32周龄组SHRs心肌组织中明显增多(P＜0.01);p-JNK mRNA表达在各组间无显著变化。
(2)较32周龄组SHRs相比,32周龄缬沙坦干预组大鼠心肌组织的GRP78、CHOP mRNA表达显著减少(P＜0.05);Caspase-12 mRNA表达两组间未见显著变化。
研究结论
(1)验证了高血压左室肥厚致左室舒张功能障碍过程中存在心肌细胞凋亡的增加,证实凋亡在高血压致心肌功能障碍过程中发挥重要作用。
(2)SHRs心肌组织GRP78的表达升高,证实高血压左室肥厚致左室舒张功能障碍过程中存在ERS的激活。
(3)SHRs心肌组织CHOP、Caspase-12表达增高,证实高血压左室肥厚致左室舒张功能障碍过程中是通过ERS相关的CHOP和Caspase-12通路介导心肌细胞凋亡。
(4)缬沙坦可能通过抑制CHOP通路的激活来减少心肌细胞的凋亡,从而发挥其逆转左室肥厚、延缓心衰出现和发展的作用。
PartⅠEndoplasmic Reticulum Stress Involved with Myocardial Apoptosis in Spontaneously Hypertensive Rats
Background
It is well known that left ventricular hypertrophy commonly occurs in hypertensive patients.However,the mechanisms in the progression from left ventricular hypertrophy to left ventricular diastolic dysfunction resulting from hypertension are not fully known.Emerging data now indicate that apoptosis occurs in the critical organs(heart,brain,or kidney) in hypertension.Therefore,we hypothesized that myocardial apoptosis may contribute the incidence of the left ventricular diastolic dysfunction.
Endoplasmic reticulum(ER) is an organelle involved in the intrinsic pathway of apoptosis and it is involved in several important functions such as the folding of secretory and membrane proteins.Various conditions can disturb the functions of the ER and result in ER stress(ERS).When ERS conditions persist,initiation of apoptotic processes are promoted by CHOP/GADD153(growth arrest and DNA damage-inducible gene 153),the Caspase-12-dependent pathway,and activation of the c-Jun NH2-terminal kinase(JNK)-dependent pathway.
Recent studies have also demonstrated that the apoptosis of cardiocytes is bound up with ERS.However,the mechanisms by which ERS lead to cell death remain enigmatic,particularly in the progression from left ventricular hypertrophy to left ventricular diastolic dysfunction resulting from hypertension.
Valsartan is a kind of angiotensis receptor blocker which not only ameliorate hypertension but also protect target organ uniquely.Based on Val-HeFT,valsartan significantly reduces the combined end point of mortality and morbidity and improves clinical signs and symptoms in patients with heart failure,when added to prescribed therapy.The mechanisms of valsartan's effects are complicated,and whether or not the mechanism related to ERS is also unclear.
Objectives
1.To definite the function of apoptosis in the progress of myocardial dysfunction induced by hypertension.
2.To observe the expression of ERS-relative factors in the myocardium in SHRs and controls.
3.To observe the relationship between the interventive effect of valsartan and ERS.
Methods
1.Establishment of animal model
1.1 Establishment of cardiac hypertrophy and animal model of the left ventricular diastolic dysfunction
Thirty SHRs(8 weeks old,SPF,male) and thirty WKY rats(8 weeks old,SPF,male) were taken from vital river laboratories.The rats were housed in cages,and had free access to standard rat diet and tap water of the center.They were maintained under conditions of standard lighting(alternating 12h light/dark cycle),temperature (22±0.5℃) and humidity(60±10%) for at least 1 week before the experiments.Then, ten SHRs or ten WKY rats were randomly killed in each group when they were 8 weeks,16 weeks and 32 weeks old.All the rats drank freely and their blood pressure was measured every 2 weeks.
1.2 the Interventive Effect of valsartan
Twenty SHRs(16weeks old,SPF,male) and ten WKY rats(16weeks old,SPF,male) were taken from vital river laboratories.Under the same raising conditions,they were feed for at least 1 week before the experiments.Twenty SHRs were randomly divided into two groups of ten.The first group of SHRs and the ten WKY rats were fed normally to grow for 32 weeks and the other group was fed valsartan(20mg/kg/d) until they were 32 weeks old.All the rats drank freely and their blood pressure was measured every 2 weeks.Both groups of SHRs were killed after the defined period of growth.
2.Measure Blood Pressure
All the rats drank freely and their blood pressure was measured every 2 weeks.
3.Blood pressure and left ventricular mass index(LVMI)
LVMI=left ventricular mass(LVM,mg)/body mass(BM,g).
4.Echocardiographic examination
At the beginning and the end of the study,transthoracic echocardiogram was performed in hypertensive and control animals.Rats were placed supine and the anterior chest wall was shaved.Echocardiograms were performed with a Hewlett-Packard Sonos 7500 sector scanner equipped with a 7.5-MHz phased-array transducer.Conventional images included 2-dimensional,M-mode,and continuous wave and pulsed Doppler images.
5.HE staining
HE staining was used to study the pathological changes in this study.
6.TUNEL staining
TUNEL staining was used to detect the expression of apoptotic cells.
7.Immunohistochemistry
Immunohistochemistry was used to detect the protein expression of GRP78,CHOP, p-JNK,Caspase-12,Caspase-3.
8.Western-blot analysis
Western-blot analysis was used to determine the protein expression of GRP78,CHOP, p-JNK,JNK,Caspase-12,Caspase-3.
9.real time RT-PCR analysis
The mRNA expressions of GRP78,CHOP,p-JNK,Caspase-12 were determined by real time RT-PCR.
Results
1.Blood pressure and LVMI
Systolic blood pressure of SHRs group were kept on at high level.Blood pressure and LVMI differed significantly(P＜0.05) in the animals of SHRs compared with the sex-matched control WKY rats.After treatment of valsartan,the level of blood pressure was obviously decreased(P＜0.05) compared with the sex-matched SHRs.
2.Establishment of the left ventricular hypertrophy and left ventricular diastolic dysfunctional model
(1).Left ventricular diastolic function variables expressed by the ratio of E-wave(early diastolic filling,early peak velocity) and A-wave(late atrial filling,atrial peak velocity) differed significantly(P＜0.05) in SHRs(16 and 32 weeks) compared with those in WKY rats(16 and 32 weeks).A significant decrease in the E-wave velocity,significant increase in the A-wave velocity,and remarkable decrease in the E/A ratio was found in SHRs(16 weeks) and remarkable increase in the E/A ratio was found in SHRs(32 weeks).Left ventricular systolic function parameters including fractional shortening (%),and ejection fraction(%) of the SHRs were no significant difference compared with the WKY rats(32 weeks).Forthermore,the thickness of interventricular septum and left ventricular posterior wall and LVMI also differed significantly(P＜0.05) compared with those in WKY rats at 16 weeks.These results demonstrated that SHRs had cardiac hypertrophy at 16 weeks of age and had left ventricular diastolic dysfunction at 32 weeks old.
(2).In the valsartan group,left ventricular diastolic function was obviously improved (P＜0.05) compared with SHRs group.
3.HE staining
With hematoxylin-eosin staining,we found that the cell size was increased significantly in the hearts of SHRs(16weeks) and cardiac muscle fibers(32weeks of SHRs) were disordered,and many of them were collapsed.In the valsartan group, myocyte hypertrophy was improved obviously.
4.TUNEL staining
To assess whether cardiac myocyte apoptosis in hypertensive heart,the tissue sections were labeled with an in situ TUNEL assay.Apoptosis was observed in both the cardiomyocyte and the endothelium of the hypertensive heart.More apoptotic cardiocytes(P＜0.05) were found from SHRs(16 weeks and 32 weeks) groups. Estimation of cardiac apoptosis revealed a nearly threefold increase in TUNEL-positive nuclei in hypertensive heart.In the valsartan group,the level of apoptosis was significantly(P＜0.05) decreased compared with SHRs group.
5.Immunohistochemistry
Immunohistochemistry studies showed that GRP78,CHOP,Caspase-12,Caspase-3 were all abundantly expressed in the myocardium of SHRs.In contrast,WKY rats exhibited modest or weak immunoreactivity for this molecule.We also found that in the myocardium of SHRs,the increasing of GRP78,CHOP,Caspase-12 and Caspase-3 positivecells paralleled with the increasing of apoptotic cells.In the valsartan group, the number of cardiac myocyte apoptosis and the expression of GRP78,CHOP and Caspase-3 were significantly(P＜0.05) decreased.However,a similar level of p-JNK protein was observed in all hypertensive and normal rats.
6.Western blot analysis of GRP78,CHOP,p-JNK,JNK,Caspase-12 and Caspase-3
The densitometric analysis of bands for GRP78,CHOP,Caspase-12,Caspase-3 but not p-JNK,JNK revealed a significant(P＜0.05,P＜0.05) increase in relative protein content in myocardium from SHRs(16weeks,32weeks) in comparison with those from WKY rats.During the initial stage of hypertension,only the protein levels of GRP78 and CHOP were upregulated(P＜0.05).In the valsartan group,protein level of GRP78, CHOP but not Caspase-12 significantly(P＜0.05) decreased compared with SHRs group.
7.real time RT-PCR analysis of GRP78,CHOP,p-JNK and Caspase-12 expression
The mRNA levels of GRP78,CHOP,Caspase-12,but not p-JNK were found to be significantly(P＜0.01) upregulated in the hypertrophic and diastolic dysfunctional heart. However,during the initial stage of hypertension,only the mRNA levels of GRP78 and CHOP were upregulated.A similar level of p-JNK mRNA was observed in all hypertensive and normal rats.In the valsartan group,mRNA levels of GRP78,CHOP were diversity(P＜0.05) compared with SHRs group but not Caspase-12.
Conclusions
1.Myocardial apoptosis plays an important role in the progress of myocardial dysfunction induced by hypertension.
2.Increase expression of GRP78,CHOP,Caspase-12 but not p-JNK in hypertensive heart paralleled with the increase of apoptotic cells.These results suggest that ERS can contribute to cardiac myocyte apoptosis in the progress of myocardial dysfunction induced by hypertension.
3.Valsartan could significantly reduced cardiac myocyte apoptosis by inhibiting the expression of CHOP.
引文
1.Poulsen SH,Andersen NH,Ivarsen PI,et al.Doppler tissue imaging reveals systolic dysfunction in patients with hypertension and apparent isolated"diastolic dysfunction.J Am Soc Echocardiogr,2003,16:724-731.
2.Olivetti G,Abbi R,Quaini F,et al.Apoptosis in the failing human heart.N Engl J Med,1997,336:1131-1141.
3.Schroder M,Kaufman RJ.ER stress and the unfolded protein response.Mutat Res,2005,569:29-63.
4.Lihong Zhao,Ackerman S.Endoplasmic reticulum stress in health and disease.Curr Opin Cell Biol,2006,18:444-452.
5.Araki E,Oyadomari S,Mori M.Impact of Endoplasmic Reticulum Stress Pathway on Pancreatic β-Cells and Diabetes Mellitus.Exp Biol Med(Maywood),2003,228:1213-1217.
6.Nakagawa T,Yuan JY.Cross-talk between two cysteine protease families.Activation of Caspase-12 by calpain in apoptosis.J Cell Biol,2000,150:887-894.
7.Rao RV,Peel A,Logvinova A,et al.Coupling endoplasmic reticulum stress to the cell death program:role of the ER chaperone GRP78.FFBS Lett,2002,514:122-128.
8.Kadowaki H,Nishitoh H,Ichijo H.Survival and apoptosis signals in ER stress:the role of protein kinases.J Chem Neuroanat,2004,28:93-100.
9.Okada K,Minamino T,Tsukamoto Y,et al.Prolonged Endoplasmic Reticulum Stress in Hypertrophic and Failing Heart After Aortic Constriction:Possible Contribution of Endoplasmic Reticulum Stress to Cardiac Myocyte Apoptosis.Circulation,2004,110:705-712.
10.Hamada H,SuzukiM,Yuasa S,et al.Dilated cardiomyopathy caused by aberrant endop lasmic reticulum quality control in mutant KDEL receptor transgenicmice.Mol CellBiol,2004,24:8007-8017.
11.Zhang C,Cai Y,Adachi MT,et al.Homocysteine induces programmed cell death in human vascular endothelial cells through activation of the unfolded protein response.J Biol Chem,2001,276:35867-35874.
12.Asim Azfer,Jianli Niu,Linda M,et al.Activation of endoplasmic reticulum stress response during the development of ischemic heart disease.Am J Physiol Heart Circ Physiol,2006,291:H1411-H1420.
13.Oyadomari S,Araki E,Mori M.Endoplasmic reticulum stress-mediated apoptosis in pancreatic beta-cells.Apoptosis,2002,7:335-345.
14.Zhenhua Li,Tao Zhang,Hongyan Dai,et al.Involvement of Endoplasmic Reticulum Stress in Myocardial Apoptosis of Streptozocin-Induced Diabeti Rats.J clin Biochem Nutr,2007,41:58-67.
15.Lindholm D,Wootz H,Korhonen L.ER stress and neurodegenerative diseases.Cell Death Differ,2006,13:385-392.
16.Lou LX,Geng B,Yu F,et al.Endoplasmic reticulum stress response is involved in the pathogenesis of stress induced gastric lesions in rats.Life Science,2007,79:1856-1864.
17.Schunkert H,Sadoshima J,Cornelius T,et al.Angiotensin Ⅱ-induced growth responses in isolated adult rat hearts:evidence for load independent induction of cardiac protein synthesis by angiotensin Ⅱ.Cire Res,1995,76:489-497.
18.Cohn Jn,Tognoni G.A randomixed trial of the angiotension-recptor blocker Valsartan in Chronic heart failure.N Engl J Med,2001,345:1667.
19.Foo RS,Mani K,Kitsis RN.Death begets failure in the heart.J Clin Invest,2005,115:565-571.
20.Xing H,Zhang S,Weinheimer C,et al.14-3-3 proteins block apoptosis and differentially regulate MAPK cascades.EMBO J,2000,19:349-358.
21.Zhang D,Gaussin V,Taffet GE,et al.TAK1 is activated in the myocardiumafter pressure overload and is sufficient to provoke heart failure in transgenic mice.Nat.Med,2000,6:556-563.
22.王华军,谢良地,许昌声等.缬沙坦治疗对自发性高血压大鼠心肌纤维化的影响.高血压杂志,2003,11:604-606.
23.Franklin SS.Ageing and hypertension:the assessment of blood pressure indices in predicting coronary heart diseases.J hypertens,1999,17(suppl 5):29-36.
24.GUEERRERO EI,ARDANAZ N,SEVILLA M A,et al.Cardiovascular effects of nebivolol in spontaneously hypertensive rats persist after treatment withdrawal.J Hypertenns,2006,24:151-158.
25.Dzau VJ.Cardiac rennin-angiotensin system.Molecular and functional aspests.AM J Med,1988,84:22-27.
26.Gonzalez A,Lopez B,Querejeta R,et al.Stimulation of cardiac apop- tosis in essential hypertension:potential role of angiotensin Ⅱ.Hypertension,2002,39:75-80.
27.Shyu KG,Chen CC,Wang BW,et al.Angiotensin Ⅱ receptor antagonist blocks the expression of connexin 43 induced by cyclical mechanical stretch in cultured neonatalrat cardiac myocytes.J Mol Cell Cardiol,2001,33:691-698.
28.Poulsen SH,Andersen NH,Ivarsen PI,et al.Doppler tissue imaging reveals systolic dysfunction in patients with hypertension and apparent "isolated"diastolic dysfunction.J Am Soc Echocardiogr,2003,16:724-731.
29.贾洪娟,王希柱,张茹.氯沙坦治疗轻中度高血压对左心室重量指数和舒张功能的影响.临床内科杂志,2005,22:18-19.
30.Iwakami M,Numano F.Regional wall motion abnormalities during early diastole in patients with hypertensive left ventricular hypertrophy:a oppler tissue echocardiographic study.J Med Dent Sci,2001,48:45-49.31.Slama M,Susic D,Varagic J,et al.Diastolic dysfunction in hypertension.Curr Opin Cardiol,2002,17:368-373.
32.Fouad F M,Slominski J M,Tarazi R C.Left ventricular diastolic function in hypertension:relation to left ventricular mass and systolic function.J Am Coll Cardiol,1984,3:1500-1506.
33.王艳,何意亭,张军,等.高血压病患者左室舒张功能的研究.中国超声医学杂志,1990,6:75-76.
34.Nakamura M,Wang NP,Zhao ZQ,et al.Preconditioning decreases Bax,PMN accumulation and apoptosis in reperfused rat heart.Circ Res,2000,45:661-670.
35.Liu JJ,Pengl,Bradley CJ,et al.Increased apop tosis in the heart of genetic hypertension associated with increased fibroblasts.Cardiovas Res,2000,45:729-735.
36.曾和松,刘正湘.卡维地洛对大鼠缺血再灌注心肌细胞凋亡及基因表达的影响.临床心血管病杂志,2004,20:220-222.
37.Fogari R,Zoppi A,Poletti L,et al.Sexual activity in hypertensive men treated with valsartan or carvedilol:a crossover study.Am J Hypertens,2001,14:27-31.
38.Der Sarkissian S,Marchand EL,Duguay D,et al.Reversal of interstitial fibroblast hyperp lasia via apoptosis in hypertensive rat heart with valsartan or enalap ril.Cardiovasc Res,2003,57:775-783.
39.Leri A,Claudio PP,Li Q.Stretch-mediated release of angiotensin Ⅱ induces myocyte apoptosis by activating p53 that enhances the local rennin-angiotensin system and decreases the Bcl-2-to-Bax protein ratio in the cell.J Clin Invest,1998,101:1326-3142.
40.Cheng W,Li B,Kajstura J.Stretch-induced programmed myocyte cell death.J Clin Invest,1995,96:2247-2259.
41.Ravassa S,Fortuno MA,Gonzalez A.Mechanisms of increased susceptibility to angiotensin Ⅱ-induced apoptosis in ventrucular cardiomyocytes of spontaneously hypertensive rats.Hypertension,2000,36:1065-1071.
42.Diep QN,El Mabrouk M,Yue P,et al.Effect of AT(1) receptor blockade on cardiac apoptosis in angiotensin Ⅱ-induced hypertension.AM J Physiol,2002,282:H1635-641.
43.Kubota T,Miyagishima M,Frye CS.Overexpression of tumor necrosis factor alpha activates both anti-and pro-apoptotic pathways in the myocardium.J Mol Cell Cardiol,2001,33:1331-1344.
44.李世英,倪新海,陈曦.血管紧张素Ⅱ促进培养的新生鼠心肌细胞表达TNF-α.高血压杂志,2003,11:161-164.
45.Yu XY,Song YH,Geng YJ,et al.Glucose induces apoptosis of cardiomyocytes via microRNA-1 and IGF-1.Biochem Biophys Res Commun,2008,376:548-552.
46.Diez J,Querejeta R,Lopez B.Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients.Circulation,2002,105:2512-2517.
47.袁木祥,孙宜萍.高血压性心脏病心肌细胞凋亡的研究进展.中国动脉硬化杂志,2006,14:86-88.
48.Beer M,Seyfarth T,Sandstede J.Absolute concentrations of high-energy phosphate metabolites in normal,hypertrophied,and failing human myocardium measured noninvasively with(31)P-SLOOP magnetic resonance spectroscopy.J Am Coll Cardiol,2002,40:1267-1274.
49.Kaufman RJ.Stress signaling from the lumen of the endoplasmic reticulum:coordination of gene transcriptional and translational controls.Gene Dev,1999,13:1211-1233.
50.Mori K.Tripartite management of unfolded proteins in the endoplasmic reticulum.Cell,2000,101:451-454.
51.Ferri KF,Kroemer G.Organelle-specific initiation of cell death pathways.Nat Cell Biol,2001,3:E255-E263.
52.Patterson C,Cyr D.Welcome to the machine:a cardiologist's introduction to protein folding and degradation.Circulation,2002,19:2741-2746.
53.Schr(o|¨)der M,Kaufman RJ.The mammalian unfolded protein response.Annu Rev Biochem,2005,74:739-789.
54.Xu C,Bailly-Maitre B,Reed JC.Endoplasmic reticulum stress:cell life and death decisions.J Clin Invest,2005,115:2656-2664.
55.Wang XZ,Lawson B,Brewer JW,et al.Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein(CHOP/GADD153).Mol Cell Biol,1996,16:4273-4280.
56.Hotamisligil GS.Role of endoplasmic reticulum stress and c-Jun NH2-terminal kinase pathways in inflammation and origin of obesity and diabetes.Diabetes,2005,54:Suppl 2 S73-78.
57.Hetz C,Russelakis-Carneiro M,Maundrell K,et al.Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein.The EMBO journal,2003,22:5435-5445.
58.Watanabe Y,Suzuki O,Haruyama T,et al.Interferon-gamma induces reactive oxygen species and endoplasmic reticulum stress at the hepatic apoptosis.J Cell Biochem,2003,89:244-253.
59.Lawrence de Koning A B,Werstuck G H,Zhou J,et al.Hyperhomocys teinemia and its role in the development of atherosclerosis.Clin Biochem,2003,36:431-441.
60.Ermak G,Davies KJ.Calcium and oxidative stress:from cell signaling to cell death.Mol Immunnol,2002,38:713-721.
61.Andreka P,Nadhazi Z,Muzes G,et al.Possible therapeutic targets in cardiac myocyte apoptosis.Curr Pharm Des,2004,10:2445-2461.
62.Yamada T,Akishita M,Pollman MJ,et al.Angiotensin Ⅱ type 2 receptor mediates vascular smooth muscle cell apoptosis and antagonizes angiotensin Ⅱ type 1 receptor action:an in vitro gene transfer study.Life Sci,1998,63:PL 289-295.
63.葛长江,胡申江,吕树铮等.伊贝沙坦逆转高血压左心室肥厚的细胞学机制.中华老年心脑血管病杂志,2006,8:51-53.
64.Dzau VJ,Re R.Tissue angiotensin system in cardiovascular medicine.A paradigm shift? Circulation,1994,89:458-470.
65.Rail I Workshop.Hypertension and cardiovascular risk factors:role of the Ang Ⅱnitricoxide interaction.Hypertension,2001,37:767-773.
66.Danial N N,Korsmeyer S J.Cell death:critical control points.Cell,2004,116:205-219.
67.Ide T,Tsutsui H,Kinugawa S,et al.Direct evidence for increased hydroxyl radicals originating from superoxide in the failing myocardium.Circ Res,2000,86:152-157.
68.Li Z,Bing OH,Long X,et al.Increased cardiomyocyte apoptosis during the transition to heart failure in the spontaneously hypertensive rat.Am J Physiol,1997,272:H2313-H2319.
69.Hamet P,Richard L,Dam TV,et al.Apoptosis in target organs in hypertension.Hypertension,1995,26:642-648.
70.Softer BA,Wright JT Jr,Pratt JH,et al.Effects of losartan on a background of hydrochlorothiazide in patients with hypertension.Hypertension,1995,26:112-117.
71.Dahl(o|¨)f B,Keller SE,Makris L,et al.Efficacy and tolerability of losartan potassium and atenolol in patients with mild to moderate essential hypertension.Am J Hypertens,1995,8:578-583.
72.谭慧琼,朱俊,于丽华,等.缬沙坦长期治疗原发性高血压病人的安全性和疗效.中国新药与临床杂志,2003,21:493-495.
73.郭冀珍,钱岳晨,马爱群等.厄贝沙坦治疗原发性高血压病人的疗效和安全性.中国新药与临床杂志,2003,21:645-648.
74.薛兆利,李明智,许法运.氯沙坦与氨氯地平的降压疗效及对左室肥厚逆转作用的比较.中国新药与临床杂志,2001,20:270-272.
75.Gustafsson AB,Gottlieb RA.Mechanisms of apoptosis in the heart.J Clin Immunol,2003,23:447-459.
76.Cui T,Nakagami H,Iwai M,et al.Pivotal role of tyrosine phosphatase SHP21 in AT2 receptor-mediated apoptosis in rat fetal vascular smooth muscle cell.Cardiovasc Res,2001,49:863-871.
77.Berridge M J,Bootman M D,Lipp P.Calcium—a life and death signal.Nature,1998,395:645-648.
78.James TN.Apoptosis in congenital heart disease.Coron Artery Dis,1997,8:599-616.
79.Wiessner C,Sauer D,Alaimo D,et al.Protective effect of a caspase inhibitor in models for cerebral ischemia in vitro and in vivo.Cell Mol Biol(Noisy-le-grand),2000,46:53-62.
80.Rabuffetti M,Sciorati C,Tarozzo G,et al.Inhibition of caspase-1-like activity by Ac-Tyr-Val-Ala-Asp-chloromethyl ketone induces long-lasting neuroprotection incerebral isehemia through apoptosis reduction and decrease of proinflammatory cytokines.J Neurosci,2000,20:4398-4404.
81.Endres M,Namura S,Shimizu-Sasamata M,et al.Attenuation of delayed neuronal death after mild focal ischemia in mice by inhibition of the caspase family.J Cereb Blood Flow Metab,1998,18:238-247.
82.Hoglen NC,Chen LS,Fisher CD,et al.Characterization of IDN-6556(3-{2-(2-tert- butyl-phenylaminooxalyl)-amino]-propionylamino}-4-oxo-5-(2,3,5,6-tetrafluoro-phen oxy)-pentanoic acid):a liver-targetedcaspase inhibitor.J Pharmacol Exp Ther,2004,309:634-640.
83.Leung-Toung R,Li W,Tam TF,et al.Thiol-dependent enzymes and their inhibitors:a review.Curr Med Chem,2002,9:979-1002.
84.Jiang X,Kim HE,Shu H,Zhao Y,et al.Distinctive roles of PHAP proteins and prothymosin-alpha in a death regulatory pathway.Science,2003,299:223-226.
85.Nguyen JT,Wells JA.Direct activation of the apoptosis machinery as a mechanism to target cancer cells.Proc Natl Acad Sci U S A,2003,100:7533-7538.
86.Gotoh,T,Mori,M.Nitric oxide and endoplasmic reticulum stress.Arterioscler Thromb Vase Biol,2006,26:1139-1446.
87.Szegezdi E,Duffy A,O'Mahoney ME,et al.ER stress contributes to ischemia-induced cardiomyocyte apoptosis.Biochem Biophys Res Commun,2006,349:1406-1411.
88.Zhang C,Kawauchi J,Adachi MT,et al.Activation of JNK and transcriptional repressor ATF3/LRF1 through the IRE1/TRAF2 pathway is implicated in human vascular endothelial cell death by homocysteine.Biochem Biophys Res Commun,2001,289:718-724.
1.Anversa P,Olivetti G,Leri A,et al.Myocyte cell deathand ventricular remodeling.Curr Opin Nephrol Hypertens,1997,6:169-176.
2.Haunstetter A.Izumo S.Apoptosis:basic mechanisms and implications for cardiovascular disease.Circ Res,1998,82:1111-1129.
3.Gonzalez A,Lopez B,Querejeta R,et al.Stimulation of cardiac apop tosis in essential hypertension:potential role of Ang Ⅱ.Hypertension,2002,39:75-80.
4.Leri A,Claudio PP,Li Q,et al.Stretch-mediated release of angiotensin Ⅱ induces myocyte apoptosis by activating p53 that enhances the local renin—angiotensin system and decreases the stimulates extracellular collagen type Ⅰ degradation and reverses Bcl-2-to-Bax protein ratio in the cell.J Clin Invest,1998,101:1326-1342.
5.De Angelis N,Fiodaliso F,Latini R,et al.Appraisal of the role of angiotensin Ⅱ and aldosterone in ventricular myocyte apoptosis in adult normotensive rat.J Mol Cell Cardiol,2002,34:1655-1665.
6.Ma Y,Hendershot L M.ER chaperone functions during normal and stress conditions.J Chem Neuroanat,2004,28:51-65.
7.Breckenridge DG,Germain M,Mathai JP,et al.Regulation of apop tosis by endop lasmic reticulum pathways.Oncogene,2003,22:8608-8618.
8.Schroder M,Kaufman RJ.ER stress and the unfolded protein response.Mutat Res,2005,569:29-63.
9.Kadowaki H,Nishitoh H,Ichijo H.Survival and apop tosis signals in ER stress:the role of protein kinases.J Chem Neuroanat,2004,28:93-100.
10.Wang XZ,Lawson B,Brewer JW,et al.Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein(CHOP/GADD153).Mol Cell Biol,1996,16:4273-4280.
11.Hotamisligil GS.Role of endoplasmic reticulum stress and c-Jun NH2-terminal kinase pathways in inflammation and origin of obesity and diabetes.Diabetes,2005,54:Suppl 2 S73-78.
12.Hetz C,Russelakis-Carneiro M,Maundrell K,et al.Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein. The EMBO J,2003,22: 5435-5445.
13.Ravassa S, Fortuno MA, Gonzalez A, et al. Mechanisms of increased susceptibility to angiotensin Il-induced apoptosis in ventricular cardiomyocytes of spontaneously hypertensive rats. Hypertension, 2000, 36: 1065-1071.
14.Fua Y C, Chia C S, Yinc S C, et al. Norepinephrine induces apoptosisin neonatal rat endothelial cells via down-regulation of Bcl-2 and activation of beta-adrenergic and caspase-2 pathways. Cardiovasc Res, 2004,61: 143-151.
15.Chae I H , Park KW, Kim H S, et al. Nitric Oxide-induced apoptosis is mediated by Bax/Bcl-2 gene expression, transition of cytochrome c, and activation of caspase-3 in rat vascular smooth muscular cells. Clin Chim Acta, 2004,341: 83-91.
16.Benavides A, Pastor D, Santos P, et al. CHOP plays a pivotal role in the astrocyte death induced by oxygen and glucose dep rivation. Glia, 2005, 52: 261-275.
17.Danial NN, Korsmeyer SJ. Cell deathxritical control points. Cell, 2004, 116:205-219.
18.Lugovskoy A A, Zhou P, Chou JJ, et al. Solution structure of the CIDE-N domain of CIDE-B and a model for CIDE-N/CIDE-N interactions in the DNA fragmentation pathway of apoptosis. Cell, 1999,99: 747-755.
19.RaffM. Cell suicide for beginners. Nature, 1998, 396: 119-122.
20.Green DR. Apoptotic pathways: paper wraps stone blunts scissors. Cell, 2000, 102:1-4.
21.Wolf BB, Green DR. Suicidal tendencies: apoptotic cell death by caspase family proteinases. J Biol Chem, 1999,274: 20049-20052.
22.Ho PK, Hawkins CJ. Mammalian initiator apoptotic caspases. FEBS J, 2005, 272:5436-5453.
23.Enari M, Sakahira H, Yokoyama H, et al. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature, 1998,391:43-50.
24.Sakahira H, Enari M, Nagata S. Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis. Nature, 1998, 391: 96-99.
25.孔建强,赵琦.细胞凋亡机制的研究进展.生物技术通报,2002,3:15-18.
26.Berridge M J,Bootman M D,Lipp P.Calcium-a life and death signal.Nature,1998,395:645-648.
27.Zhang H,Li Q,Li Z,et al.The protection of Bcl-2 overexpression on rat cortical neuronal injury caused by analogous ischemia/reperfusion in vitro.Neurosci Res,2008,62:140-146.
28.Verhagen A M,Eckert PG,Paunch M.Identification of DIABLO,a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins.Cell,2000,102:43-53.
29.Diep QN,ElMabroukM,Yue P,et al.Effect of AT(1) receptor blockade on cardiac apoptosis in angiotensin Ⅱ-induced hypertension.Am J Physiol,2002,282:H1635-H1641.
30.Fortu.noMA,Ravassa S,Fortu.no A,et al.Cardiomyocyte apop totic cell death in arterial hypertension:mechanisms and potential management.Hypertension,2001,38:1406-1412.
31.徐菲菲,刘秀华,王彦珍等.肌原纤维调节因子-1在心肌肥大中的作用研究.中国病理生理杂志,2006,22:443-447.
32.Dzau VJ,Mukoyama M,Pratt RE.Molecular biology of angiotensin receptors:target for drug research.J Hypertens,1994,12(suppl):1-5.
33.Paradis P,DaliyoucefN.Over expression of and Ⅱ type Ⅰ receptor in cardiomyocyte induces cardiac hypertrophy and remodeling.Proc Natl Acad Sci USA,2000,97:931-936.
34.Fiordaliso F,Cuccovillo I,Bianchi R et al.Cardiovascular oxidative stress is reduced by an ACE inhibitor in a rat model of streptozotocin-induced diabetes.Life Sci,2006,79:121-129.
35.Yamamoto K,Shioi T,Uchiyama K et al.Attenuation of virus-induced myocardial injury by inhibition of the angiotensin Ⅱ type 1 receptor signal and decreased nuclear factor-kappa B activation in knockout mice.J Am Coll Cardiol,2003,42:2000-2006.
36.Hengartner MO.Apoptosis:corralling the corpses.Cell,2001,104:325-328.
37.Chen G, Goeddel DV. TNF-R1 signaling: a beautiful pathway. Science, 2002, 296:1634-1635.
38.Tsukumo SI, Yonehara S. Requirement of cooperative functions of two repeated death effector domains in caspase-8 and in MC159 for induction and inhibition of apoptosis, respectively. Genes Cells, 1999,4: 541-549.
39.Fu YC, Chi CS, Yin SC, et al. Norepinephrine induces apoptosis in neonatal rat cardiomyocytes through a reactive oxygen species-TNF alpha-caspase signaling pathway. Cardiovasc Res, 2004,62: 558-567.
40.Cigola E, Kajstura J, Li B, et al. Angiotensin II activates p rogrammed myocyte cell death in vitro. Exp Cell Res, 1997,231: 363-371.
41.Nitahara JA, ChengW, liu Y, et al. Intracellular calcium, DNase activity and myocyte apoptosis in the aging Fischer 344 rats. J Mol Cell Cardiol, 1998, 30:519-535.
42.Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic reticulum resident kinase. Nature, 1999, 397: 271-274.
43.Tang JR, NakamuraM, Okura T, et al. Mechanism of oxidative stress-induced GADD153 gene exp ression in vascular smooth muscle cells. Biochem Biophys Res Commun, 2002, 290: 1255-1259.
44.UbedaM, Habener JF. CHOP gene expression in responseto endop lasmic-reticular stress requires NFY interaction with different domains of a conserved DNA-binding element. Nucleic Acids Res, 2000,2:4987-4997.
45.CorazzariM, Lovat PE, Oliverio S,et al. Fenretinide:a p53 independent way to kill cancer cells. Biochem Biophys Res Commun, 2005,331: 810-815.
46.Grishko V, Pastukh V, Solodushko V, et al. Apop toticcascade initiated by angiotensin II in neonatal cardiomyocytes:role of DNA damage. Am J Physiol, 2003,285: H2364- H2372.
47.Pang JJ, Xu RK, Xu XB, et al. Hexarelin protects rat cardiomyocytes from angiontensin II -induced apop tosisin vitro. Am J Physiol, 2004,286: H1063-H1069.
48.Qin F, Patel R, Yan C, et al. NADPH oxidase is involved in Ang II induced apoptosis in H9C2 cardiac muscle cells:Effects of apocynin.Free Radical BiolMed,2006,40:236-246.
49.Guan QH,PeiDS,Xu TL,et al.Brain ischemia reperfusion-induced exp ression of DP5 and interaction with Bcl-2,thus freeing Bax from Bcl-2/Bax dimmers are mediated by c-Jun N-terminal kinase(JNK) pathway.Neurosci Lett,2006,393:226-236.
50.Reed JC.Proapoptotic multidomain Bcl-2/Bax-family proteins:mechanisms,physiological roles,and therapeutic opportunities.Cell Death Differ,2006,13:1378-1386.
51.Nakagawa T,Zhu H,Morishma N.Caspase-12 mediates endoplasmic reticulum specific apoptosis and cytotoxicity by amyloid-beta.Nature,2000,403:98-103.
52.Martinon F,Tschopp J.Inflammatory caspases and inflammasomes:master switches of inflammation.Cell Death Differ,2007,14:10-22.
53.Justo P,Lorz C,Sanz A,et al.Intracellular mechanisms of cyclosporin A-induced tubular cell apoptosis.J Am Soc Nephrol,2003,14:3072-3080.
54.Rao RV,Hermel E,Castro-Obregon S,et al.Coupling endoplasmic reticulum stress to the cell death program.Mechanism of caspase activation.J Biol Chem,2001,276:33869-33874.
55.Yoneda T,Imaizumi K,Oono K,et al.Activation of caspase-12,an endoplastic reticulum(ER) resident caspase,through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress.J Biol Chem,2001,276:13935-13940.
56.Morishima N,Nakanishi K,Takenouchi H,et al.An endoplasmic reticulum stress-specific caspase cascade in apoptosis,cytochrome c-independent activation of caspase-9 by caspase-12.J Biol Chem,2002,277:34287-34294.
57.Ermak G,Davies KJ.Calcium and oxidative stress:from cell signaling to cell death.Mol Immunol,2002,8:713-721.
58.Ferri KF,Kroemer G.Organelle-specific initiation of cell death pathways.Nat Cell Biol,2001,3:E255-E263.
59.Breckenridge DG,Germain M,Mathai JP,et al.Regulation of apoptosis by endop lasmic reticulum pathways.Oncogene,2003,22:8608-8618.
60.Tsuruma K,Nakagawa T,Morimoto N,et al.Glucocorticoid modulatory element-binding protein 1 binds to initiator procaspases and inhibits ischemia-induced apoptosis and neuronal injury.J Biol Chem,2006,281:11397-11404.
61.Di Sano F,Ferraro E,Tufi R,Achsel T,Piacentini M,Cecconi F.Endoplasmic reticulum stress induces apoptosis by an apoptosome dependent but caspase-12-independent mechanism.J Biol Chem,2006,281:2693-2700.
62.Obeng E A,L H Boise.Caspase-12 and caspase-4 are not required for caspase-dependent endoplasmic reticulum stress-induced apoptosis.J Biol Chem,2005,280:29578-29587.
63.Hitomi J,Katayama T,Eguchi Y,et al.Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death.J.Cell Biol,2004,165:347-356.
64.Momoi T.Caspases involved in ER stress-mediated cell death.J Chem Neuroanat,2004,28:101-105.
65.Chunyan Xu,Beatrice Bailly-Maitre,John C Reed.Endoplasmic reticulum stress:cell life and death decisions.J Clin Invest,2005,115:2656-2664.
66.Rizzuto R,Pinton P,Carrington W,et al.Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca~(2+) responses Science,1998,280:1763-1766.
67.Verkhratsky A,Toescu EC.Endoplasmic reticulum Ca~(2+)homoestasis and neuronal death.J Cell Mol Med,2003,7:351-361.
68.Newmeyer DD,Ferguson-Miller S.Mitochondria:releasing power for life and unleashing the machineries of death.Cell,2003,112:481-490.
69.Abad MF,Di Benedetto G,Magalhaes PJ,et al.Mitochondrial pH monitored by a new engineered green fluorescent protein mutant.J Biol Chem,2004,279:11521-11529.
70.Pinton P,Ferrari D,Rapizzi E,et al.The Ca~(2+)concentration of the endoplasmic reticulum is a key determinant of ceramide-induced apoptos-is:significance for the molecular mechanism of Bcl-2 action.EMBO J,2001,20:2690-2701.
71.Oakes SA,Opferman JT,Pozzan T,et al.Regulation of endoplasmic reticulum Ca~(2+)dynamics by proapoptotic BCL-2 family members.Biochem Pharmacol,2003,66:1335-1340.
72.Kitao Y,Ozawa K,Miyazaki M,et al.Expression of the endoplasmic reticulum molecular chaperone(ORP 150) rescues hippocampal neurons from glutamate toxicity.J Clin Invest,2001,108:1439-1450.
73.Xie Q,Khaoustov Ⅵ,Chung CC,et al.Effect of tauroursodeoxycholicacid on ER stress-induced Caspase-12 activation.Hepatology,2002,36:592-601.
74.Gaido ML,Cidlowski JA.Identification,purification,and characteriz-eation of a calcium-dependent endonuclease(NUC18) from apoptotic rat thymocytes.NUC18 is not histone H2B.J Biol Chem,1991,266:18580-18585.
75.Enslen H,Soderling TR.Roles of calmodulin-dependent protein kinases and phosphatase in calcium-dependent transcrip tion of immediate early genes.J Biol Chem,1994,269:20872-20877.
76.ShengM,McFadden G,Greenberg ME.Membrane depolarization and calcium induce c-fos transcription via phosphorylation of transcription factor CREB.Neuron,1990,4:571-582.
77.Hengartner MO.Apoptosis,Death cycle and Swiss army knives.Nature,1998,391:441-442.
78.Chae I H,Park KW,Kim H S,et al.Nitric Oxide-induced apoptosis is mediated by Bax/Bcl-2 gene expression,transition of cytochrome c,and activation of caspase-3 in rat vascular smooth muscular cells.Clin Chim Acta,2004,341:83-91.
79.Yaoita H,Ogawa K,Maehara K,et al.Attenuation of ischemia/reperfusion injury in rats by a caspase inhibitor.Circulation,1998,97:276-281.
80.Holly TA,Drincic A,Byun Y,et al..Caspase inhibition reduces myocyte cell death induced by myocardial ischemia and reperfusion in vivo.J Mol Cell Cardiol,1999,31:1709-1715.
81.Huang JQ,Radinovic S,Rezaiefar P,et al.In vivo myocardial infarct size reduction by a caspase inhibitor administered after the onset of ischemia.Eur J Pharmacol,2000,402:139-142.
82.Wencker D,Chandra M,Nguyen K,et al.A mechanistic role for cardiac myocyte apoptosis in heart failure.Cell,2003,111:1497-1504.
83.Hayakawa Y,Chandra M,Miao W,et al.Inhibition of cardiac myocyte apoptosis improves cardiac function and abolishes mortality in the peripartum cardiomyopathy of Galpha(q) transgenic mice.Circulation,2003,108:3036-3041.
84.Foo RS,Mani K,Kitsis RN.Death begets failure in the heart.J Clin Invest,2005,115:565-571.