ObjectiveAutophagy is activated in ischemic heart diseases, but its dynamics and functional roles remain unclear and controversial. In this study, we investigated the dynamics and role of autophagy and the mechanism(s), if any, during postinfarction cardiac remodeling.Methods and resultsAcute myocardial infarction (AMI) was induced by ligating left anterior descending (LAD) coronary artery. Autophagy was found to be induced sharply 12–24 hours after surgery by testing LC3 modification and Electron microscopy. P62 degradation in the infarct border zone was increased from day 0.5 to day 3, and however, decreased from day 5 until day 21 after LAD ligation. These results indicated that autophagy was induced in the acute phase of AMI, and however, impaired in the latter phase of AMI. To investigate the significance of the impaired autophagy in the latter phase of AMI, we treated the mice with Rapamycin (an autophagy enhancer, 2.0 mg/kg/day) or 3-methyladenine (3MA, an autophagy inhibitor, 15 mg/kg/day) one day after LAD ligation until the end of experiment. The results showed that Rapamycin attenuated, while 3MA exacerbated, postinfarction cardiac remodeling and dysfunction respectively. In addition, Rapamycin protected the H9C2 cells against oxygen glucose deprivation in vitro. Specifically, we found that Rapamycin attenuated NFκB activation after LAD ligation. And the inflammatory response in the acute stage of AMI was significantly restrained with Rapamycin treatment. In vitro, inhibition of NFκB restored autophagy in a negative reflex.ConclusionSustained myocardial ischemia impairs cardiomyocyte autophagy, which is an essential mechanism that protects against adverse cardiac remodeling. Augmenting autophagy could be a therapeutic strategy for acute myocardial infarction.

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BACKGROUND AND PURPOSESirtuin 6 (SIRT6) is involved in regulation of glucose and fat metabolism. However, its possible contribution to cardiac dysfunction remains to be determined. In the present study, the effect of SIRT6 on cardiac hypertrophy induced by angiotensin II (AngII) and the underlying molecular mechanisms were investigated. EXPERIMENTAL APPROACHThe expression and deacetylase activity of SIRT6 were measured in hypertrophic cardiomyocytes induced by AngII. After SIRT6 overexpression by transfection, or depletion by RNA interference in neonatal rat cardiomyocytes, cellular hypertrophy was monitored by measuring cell surface area and the mRNA levels of hypertrophic biomarkers. Further, the interaction between SIRT6 and the transcription factor NF-kB was investigated by co-immunoprecipitation, confocal immunofluorescence microscopy and luciferase reporter gene assay. The expression and deacetylase activity of SIRT6 were measured in vivo, using the abdominal aortic constriction (AAC) model of cardiac hypertrophy in rats. KEY RESULTSIn AngII-induced hypertrophic cardiomyocytes and also in AAC-induced hypertrophic hearts, the expression of SIRT6 protein was upregulated, while its deacetylase activity was decreased. Overexpression of wild-type SIRT6 but not its catalytically inactive mutant, attenuated AngII-induced cardiomyocyte hypertrophy. We further demonstrated a physical interaction between SIRT6 and NF-kB catalytic subunit p65, whose transcriptional activity could be repressed by SIRT6 overexpression. CONCLUSIONS AND IMPLICATIONSOur findings suggest that SIRT6 suppressed cardiomyocyte hypertrophy in vitro via inhibition of NF-kB-dependent transcriptional activity and that this effect was dependent on its deacetylase activity.

Edited by Zhijie ChangKeywords: Nmnat2 Cardiac hypertrophy Sirtuin 6 NAD Ang II a b s t r a c tThe discovery of sirtuins (SIRT), a family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases, has indicated that intracellular NAD level is crucial for the hypertrophic response of cardiomyocytes. Nicotinamide mononucleotide adenylyltransferase (Nmnat) is a central enzyme in NAD biosynthesis. Here we revealed that Nmnat2 protein expression and enzyme activity were down-regulated during cardiac hypertrophy. In neonatal rat cardiomyocytes, overexpression of Nmnat2 but not its catalytically inactive mutant blocked angiotensin II (Ang II)-induced cardiac hypertrophy, which was dependent on activation of SIRT6 through maintaining the intracellular NAD level. Our results suggested that modulation of Nmnat2 activity may be beneficial in cardiac hypertrophy.

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