«上一篇/Previous Article|本期目录/Table of Contents|下一篇/Next Article»

《心脏杂志》[ISSN:1009-7236/CN:61-1268/R]

期数:

2014年第1期

页码:

15-20

栏目:

基础研究

出版日期:

2013-12-02

文章信息/Info

Title:

Cyclosporine protects against myocardial ischemia/reperfusion injury

作者:

尹巧香¹; 王 恒²; 裴志勇³; 赵玉生⁴

(空军总医院：1.干部病房心内科，2.神经内科，北京 100142；3.北京军区总医院干部病房一科，北京100700；4.解放军总医院老年心血管病研究所，北京 100853)

Author(s):

YIN Qiao-xiang¹;  WANG Heng²;  PEI Zhi-yong³;  ZHAO Yu-sheng⁴

(1.Department of Geriatric Cardiology, 2.Department of Neurology, General Hospital of Air Force, Beijing 100142, China; 3.Department of Geriatric Cardiology, General Hospital, Beijing Military Area Command, Beijing 100700, China; 4.Institute of Geriatric Cardiology, PLA General Hospital, Beijing 100853, China)

关键词:

环孢菌素A; 心肌缺血/再灌注损伤; 他可英司; 线粒体; 小型猪

Keywords:

cyclosporin A;  myocardial ischemia/reperfusion injury;  FK-506;  mitochondria;  swine

分类号:

R979.5

DOI:

-

文献标识码:

A

摘要:

目的:研究环孢菌素A(CsA)拮抗小型猪心肌缺血/再灌注损伤(MI/RI)的作用及可能的机制。方法:经皮球囊封堵冠状动脉左前降支制备小型猪MI/RI模型。将存活的动物随机分为3组：即对照组(n=4)、CsA组(n=6)及他可英司(FK-506)组(n=6)，分别静滴生理盐水100 ml、25 mg/kg CsA及1 mg/kg FK-506。所有动物均经90 min缺血和3 h再灌注。通过病理检查评估心肌梗死(MI)面积。用免疫组化染色法检测心肌细胞凋亡。用透射电子显微镜观察各组心肌细胞线粒体的形态。结果:CsA组MI的面积比对照组［(7.5±0.6) cm2 vs. (10.5±2.6) cm2］和FK-506组［(7.5±0.6) cm2 vs. (9.6±2.7) cm2］明显减少(P<0.01)；CsA组心肌细胞的凋亡率(%)比对照组［(11.9±1.88)% vs. (22.3±1.66)%］和FK-506组［(11.9±1.88)% vs. (19.2±1.82)%］明显下降(P<0.01)。透射电子显微镜检查显示，CsA组能维持线粒体的形态，线粒体坍塌的百分率为(20%±7%)，比对照组(53%±12%)和FK-506组(47%±9%)明显减少(P<0.01)。结论:CsA可能对MI/RI具有拮抗作用，其机制可能是通过抑制线粒体膜通透性转换孔(mPTP)，保持线粒体形态完整而实现，此种效应不依赖于钙调磷酸酶抑制途径。

Abstract:

AIM:To evaluate the effects and mechanisms of cyclosporin A (CsA) in protecting against myocardial ischemia/reperfusion injury in a swine model. METHODS: Models were established by coronary angioplasty percutaneous balloon occlusion of the left anterior descending artery (LAD). Swine that survived after myocardial ischemia/reperfusion were divided into three groups: control (n=4), CsA (n=6) and FK-506 (n=6). The three groups received, respectively, saline vehicle 100 ml, 25 mg/kg CsA and 1 mg/kg FK-506. All animals underwent 90 min of regional ischemia and 3 h of reperfusion. Myocardial infarct size and apoptotic cell death were determined by pathological assessment and immunohistopathology. Transmission electron microscopy was used to evaluate morphologic differences in the mitochondria between the groups. RESULTS: Infarct size in CsA group was significantly reduced compared with that in control group ［(7.5±0.6) cm2 vs.(10.5±2.6) cm2, P<0.01］ and FK-506 group ［(7.5±0.6) cm2 vs.(9.6±2.7) cm2, P<0.019］. Apoptotic index in CsA group was also attenuated compared with that in control group ［(11.9±1.88)% vs.(22.3±1.66)%, P<0.01］ and FK-506 group ［(11.9±1.88)% vs.(19.2±1.82)%, P<0.01］. Transmission electron microscopy revealed a preservation of normal mitochondrial morphology and a reduction in the percentage of disrupted mitochondria in CsA group (20%±7%) compared with those in control group (53%±12%) and FK-506 group (47%±9%). CONCLUSION: Cyclosporine A-induced mPTP inhibition preserves mitochondrial morphology after myocardial ischemia/reperfusion and limits myocyte necrosis and apoptosis. These effects are independent of calcineurin inhibition.

参考文献/References

[1]Ruiz-Meana M,Inserte J,Fernandez-Sanz C,et al.The role of mitochondrial permeability transition in reperfusion-induced cardiomyocyte death depends on the duration of ischemia[J].Basic Res Cardiol,2011,106(6):1259-1268.
[2]Argaud L,Gateau-Roesch O,Muntean D,et al. Specificinhibition of the mitochondrial permeability transition prevents lethal reperfusion injury[J].J Mol Cell Cardiol,2005,38(2):367-374.
[3]Leshnower BG,Kanemoto S,Matsubara M,et al.Cyclosporine preserves mitochondrial morphology after myocardial ischemia/reperfusion independent of calcineurin inhibition[J].Ann Thor Surg,2008,86(4):1286-1292.
[4]Piot C,Criosille P,Staat P,et al.Effect of cyclosporine on reperfusion injury in acute myocardial infarction[J].N Engl J Med,2008,359(5):473-481.
[5]Halestrap AP.A pore way to die:the role of mitochondria in reperfusion injury and cardioprotection[J].Biochem Soc Trans,2010,38(4):841-860.
[6] Perrelli MG,Pagliaro P,Penna C.Ischemia/reperfusion injury and cardioprotective mechanisms:Role of mitochondria and reactive oxygen species[J].World J Cardiol,2011,3(6):186-200.
[7]Waldmeier PC,Feldtrauer JJ,Qian T.Inhibition of the mitochondrial permeability transition by the nonimmunosuppressive cyclosporin derivative NIM811[J].Mol Pharmacol,2002,62(1):22-29.
[8]Nathan M,Friehs I,Choi YH,et al.Cyclosporin A but not FK-506 protects against dopamine-induced apoptosis in the stunned heart[J].Ann Thorac Surg,2005,79(5):1620-1626.
[9]Gomez L, Thibault H,Gharib A,et al.Inhibition of mitochondrial permeability transitionimproves functional recovery and reduces mortality following acute myocardialinfarction in mice[J].Am J Physiol Heart Circ Physiol,2007,293(3):H1654-H1661.
[10]Perrelli MG,Pagliaro P,Penna C. Ischemia/reperfusion injury and cardioprotective mechanisms:Role of mitochondria and reactive oxygen species[J].World J Cardiol,2011,3(6):186-200.
[11]Malouttre S,Dube H,Selwood D,et al.Mitochondrial targeting of cyclosporin A enables selective inhibitionof cyclophilin-D and enhanced cytoprotection after glucose and oxygen deprivation[J].Biochem J,2009,425(1):137-148.

备注/Memo

备注/Memo:

收稿日期：2013-07-04.基金项目：国家高技术研究发展（863）计划项目资助（2006AA02A105） 作者简介：尹巧香，副主任医师，博士 Email：zmyyqx-20041129@163.com

常用功能

更新日期/Last Update: 2014-01-20