Department of Surgical Intensive Care Unit, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
Chin Med J (Engl). 2009 Oct 5;122(19):2372-9.
The loss of cardiac myocytes is one of the mechanisms involved in acute myocardial infarction (AMI)-related heart failure. Autophagy is a common biological process in eukaryote cells. The relationship between cardiac myocyte loss and autophagy after AMI is still unclear. Carvedilol, a non-selective alpha1- and beta-receptor blocker, also suppresses cardiac myocyte necrosis and apoptosis induced by ischemia. However, the association between the therapeutic effects of carvedilol and autophagy is still not well understood. The aim of the present study was to establish a rat model of AMI and observe changes in autophagy in different zones of the myocardium and the effects of carvedilol on autophagy in AMI rats.
The animals were randomly assigned to a sham group, an AMI group, a chloroquine intervention group and a carvedilol group. The AMI rat model was established by ligating the left anterior descending coronary artery. The hearts were harvested at 40 minutes, 2 hours, 24 hours and 2 weeks after ligation in the AMI group, at 40 minutes in the chloroquine intervention group and at 2 weeks in other groups. Presence of autophagic vacuoles (AV) in the myocytes was observed by electron microscopy. The expression of autophagy-, anti-apoptotic- and apoptotic-related proteins, MAPLC-3, Beclin-1, Bcl-xl and Bax, were detected by immunohistochemical staining and Western blotting.
AVs were not observed in necrotic regions of the myocardium 40 minutes after ligation of the coronary artery. A large number of AVs were found in the region bordering the infarction. Compared with the infarction region and the normal region, the formation of AV was significantly increased in the region bordering the infarction (P < 0.05). The expression of autophagy- and anti-apoptotic-related proteins was significantly increased in the region bordering the infarction. Meanwhile, the expression of apoptotic-related proteins was significantly increased in the infarction region. In the chloroquine intervention group, a large number of initiated AVs (AVis) were found in the necrotic myocardial region. At 2 weeks after AMI, AVs were frequently observed in myocardial cells in the AMI group, the carvedilol group and the sham group, and the number of AVs was significantly increased in the carvedilol group compared with both the AMI group and the sham group (P < 0.05). The expression of autophagy- and anti-apoptotic-related proteins was significantly increased in the carvedilol group compared with that in the AMI group, and the positive expression located in the infarction region and the region bordering the infarction.
AMI induces the formation of AV in the myocardium. The expression of anti-apoptosis-related proteins increases in response to upregulation of autophagy. Carvedilol increases the formation of AVs and upregulates autophagy and anti-apoptosis of the cardiac myocytes after AMI.
心肌细胞的丢失是急性心肌梗死（AMI）相关心力衰竭的机制之一。自噬是真核细胞中常见的生物学过程。AMI 后心肌细胞丢失与自噬之间的关系尚不清楚。卡维地洛是一种非选择性的α 1 和β受体阻滞剂，也能抑制缺血诱导的心肌细胞坏死和凋亡。然而，卡维地洛的治疗效果与自噬之间的关联仍不太清楚。本研究的目的是建立 AMI 大鼠模型，并观察不同心肌区域自噬的变化以及卡维地洛对 AMI 大鼠自噬的影响。
动物随机分为假手术组、AMI 组、氯喹干预组和卡维地洛组。结扎左前降支冠状动脉建立 AMI 大鼠模型。AMI 组于结扎后 40 分钟、2 小时、24 小时和 2 周，氯喹干预组于 40 分钟，其他组于 2 周取心脏。电镜观察心肌细胞自噬小体（AV）的存在。通过免疫组化染色和 Western blot 检测自噬、抗凋亡和凋亡相关蛋白 MAPLC-3、Beclin-1、Bcl-xl 和 Bax 的表达。
冠状动脉结扎后 40 分钟，坏死区未见 AV。梗死区边缘可见大量 AV。与梗死区和正常区相比，梗死区边缘的 AV 形成明显增加（P<0.05）。梗死区边缘自噬和抗凋亡相关蛋白表达明显增加。同时，凋亡相关蛋白在梗死区表达明显增加。氯喹干预组在坏死心肌区发现大量起始 AV（AVis）。AMI 后 2 周，AMI 组、卡维地洛组和假手术组心肌细胞中常可见 AV，卡维地洛组 AV 数明显多于 AMI 组和假手术组（P<0.05）。与 AMI 组相比，卡维地洛组自噬和抗凋亡相关蛋白的表达明显增加，阳性表达位于梗死区和梗死区边缘。
AMI 诱导心肌中 AV 的形成。自噬增加导致抗凋亡相关蛋白表达增加。卡维地洛增加 AMI 后 AV 的形成，并上调心肌细胞的自噬和抗凋亡作用。
