Department of Cardiology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
Cardiovasc Res. 2011 Jul 15;91(2):330-9. doi: 10.1093/cvr/cvr073. Epub 2011 Mar 15.
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.
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.
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.
在缺血性心脏病中，心肌细胞会发生自噬，但心肌梗死后其动态变化及其功能作用仍不清楚。我们观察了心肌细胞自噬的动态变化，并研究了其在梗死后心脏重构过程中的作用。
通过结扎左冠状动脉在小鼠中诱导心肌梗死。在亚急性期和慢性期（分别为梗死后 1 周和 3 周），自噬均被激活，微管相关蛋白 1 轻链 3-II（LC3-II）、p62 和组织蛋白酶 D 的表达上调以及电镜检查结果均表明了这一点。自噬的激活，特别是消化步骤，在梗死后 1 周的心肌细胞中尤为明显，尤其是在梗死区周围的心肌细胞中，而自噬体的形成则在梗死后 3 周更为明显。巴弗洛霉素 A1（一种自噬抑制剂）显著加重梗死后的心脏功能障碍和重构。该组的心肌肥厚加剧，并伴有心房利钠肽在心室中的表达增加。在这些心脏中，自噬发现（即 LC3-II 的表达和自噬体的存在）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）的治疗带来了相反的结果，包括减轻心脏功能障碍和不良重构。巴弗洛霉素 A1 和雷帕霉素的联合治疗抵消了它们对梗死后心脏中心肌细胞自噬和心脏重构的影响。
这些发现表明，心肌细胞自噬是一种内在机制，可防止梗死后心脏重构的进展，这意味着增强自噬可能是一种治疗策略。
