The role of autophagy emerging in postinfarction cardiac remodelling
The role of autophagy emerging in postinfarction cardiac remodelling
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DOI：
10.1093/cvr/cvr073
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发表时间：
2011-07-15
影响因子：
10.8
通讯作者：
Minatoguchi, Shinya
中科院分区：
文献类型：
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作者：
Kanamori, Hiromitsu;Takemura, Genzou;Minatoguchi, Shinya
AIMS在缺血性心脏病的心肌细胞中被激活，但其在心肌梗死后的动力学和功能作用尚不清楚。观察心肌细胞自噬的动态变化，探讨其在心肌梗死后重构中的作用。方法与结果结扎左冠状动脉建立小鼠心肌梗死模型。在亚急性期和慢性期(分别为梗塞后1周和3周)，存活的心肌细胞中发现自噬被激活，表现为微管相关蛋白-1轻链3-II(LC3-II)、p62和组织蛋白酶D的表达上调，并通过电子显微镜观察。自噬的激活，尤其是消化步骤，在梗塞后1周的心肌细胞中显著，尤其是在梗死区边缘的心肌细胞，而在梗塞后3周，自噬小体的形成显著。巴菲霉素A1(一种自噬抑制剂)显著加重了梗死后的心功能障碍和重塑。本组患者心肌肥厚加重，并伴有心钠素表达增强。在这些心脏中，自噬发现(即Lc3-II的表达和自噬小体的存在)减少，而AMP激活的蛋白激酶的激活增强。雷帕霉素(一种自噬增强剂)的治疗产生了相反的结果，包括缓解心脏功能障碍和不良的重构。巴非霉素A1和雷帕霉素联合治疗可抵消心肌细胞自噬和心肌重构的影响。结论心肌细胞自噬是防止心肌梗死后心脏重构进展的内在机制，提示加强自噬可能是一种治疗策略。
Aims Autophagy is activated in cardiomyocytes in ischaemic heart disease, but its dynamics and functional roles remain unclear after myocardial infarction. We observed the dynamics of cardiomyocyte autophagy and examined its role during postinfarction cardiac remodelling.Methods and results Myocardial infarction was induced in mice by ligating the left coronary artery. During both the subacute and chronic stages (1 and 3 weeks postinfarction, respectively), autophagy was found to be activated in surviving cardiomyocytes, as demonstrated by the up-regulated expression of microtubule-associated protein-1 light chain 3-II (LC3-II), p62 and cathepsin D, and by electron microscopic findings. Activation of autophagy, specifically the digestion step, was prominent in cardiomyocytes 1 week postinfarction, especially in those bordering the infarct area, while the formation of autophagosomes was prominent 3 weeks postinfarction. Bafilomycin A1 (an autophagy inhibitor) significantly aggravated postinfarction cardiac dysfunction and remodelling. Cardiac hypertrophy was exacerbated in this group and was accompanied by augmented ventricular expression of atrial natriuretic peptide. In these hearts, autophagic findings (i.e. expression of LC3-II and the presence of autophagosomes) were diminished, and activation of AMP-activated protein kinase was enhanced. Treatment with rapamycin (an autophagy enhancer) brought about opposite outcomes, including mitigation of cardiac dysfunction and adverse remodelling. A combined treatment with bafilomycin A1 and rapamycin offset each effect on cardiomyocyte autophagy and cardiac remodelling in the postinfarction heart.Conclusion These findings suggest that cardiomyocyte autophagy is an innate mechanism that protects against progression of postinfarction cardiac remodelling, implying that augmenting autophagy could be a therapeutic strategy.