Treatment with the autophagy enhancer rapamycin mitigated postinfarction cardiac dysfunction and adverse remodelling in mice, whereas the inhibitor bafilomycin A1 significantly aggravated them.
Does modulating autophagy with rapamycin or bafilomycin A1 improve postinfarction cardiac remodeling in mice?
Cardiomyocyte autophagy acts as an innate protective mechanism against postinfarction cardiac remodeling, and its pharmacological enhancement mitigates adverse remodeling in mice.
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.
Kanamori et al. (Tue,) conducted a other in Myocardial infarction. Bafilomycin A1 and Rapamycin was evaluated on Postinfarction cardiac dysfunction and remodelling. Treatment with the autophagy enhancer rapamycin mitigated postinfarction cardiac dysfunction and adverse remodelling in mice, whereas the inhibitor bafilomycin A1 significantly aggravated them.
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