环孢菌素A拮抗心肌缺血/再灌注损伤的作用

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)cm2vs.(10.5±2.6)cm2]和FK-506组[(7.5±0.6)cm2vs.(9.6±2.7)cm2]明显减少(P0.01);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(P0.01)。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(P0.01)。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。

Cyclosporine protects against myocardial ischemia/reperfusion injury

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.