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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(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。
Objective: To investigate the effect of cyclosporin A (CsA) on myocardial ischemia / reperfusion injury (MI / RI) and its possible mechanism. Methods: Minipig MI / RI model was prepared by percutaneous balloon occlusion of left anterior descending artery of coronary artery. Survival animals were randomly divided into three groups: control group (n = 4), CsA group (n = 6) and FK-506 group (n = 6) 25 mg / kg CsA and 1 mg / kg FK-506. All animals were subjected to ischemia at 90 min and reperfusion at 3 h. Myocardial infarction (MI) area was assessed by pathology. Cardiomyocyte apoptosis was detected by immunohistochemical staining. Transmission electron microscopy was used to observe the morphology of mitochondria in each group. Results: The area of MI in CsA group was significantly lower than that in control group [(7.5 ± 0.6) cm2 vs (10.5 ± 2.6) cm2] and FK 506 group [(7.5 ± 0.6) cm2 vs (9.6 ± 2.7) 0.01). The apoptotic rate of cardiomyocytes in CsA group was significantly higher than that in control group [(11.9 ± 1.88)% vs (22.3 ± 1.66)%] and FK-506 group [(11.9 ± 1.88)% vs 1.82)%] decreased significantly (P <0.01). Transmission electron microscopy revealed that the mitochondria morphology was maintained in the CsA group, with mitochondrial collapse at (20% ± 7%), significantly greater than those in the control group (53% ± 12%) and FK-506 group (47% ± 9%) Decrease (P <0.01). CONCLUSIONS: CsA may have an antagonistic effect on MI / RI. The mechanism may be through the inhibition of mitochondrial membrane permeability transition pore (mPTP) and the maintenance of mitochondrial integrity, which is independent of the calcineurin inhibition pathway.