Abstract
Introduction: Metformin activates AMP-activated protein kinase (AMPK) to improve cardiac function during ischemia and reperfusion (I/R). We reported that Sestrin2 (Sesn2) is associated with AMPK and maintains oxidative phosphorylation (OXPHOS) under I/R stress. The role of age-related Sesn2-AMPK signaling in the beneficial actions of metformin on ischemic insults remains unknown. Hypothesis: Metformin maintains mitochondrial integrity and limits cardiac damage caused by ischemic insults through the Sesn2-AMPK signaling pathway. Methods: Young (3-6 months) and aged (22-24 months) C57BL/6J wild type mice, and 3 months of Sesn2 f/f and cardiomyocyte-specific Sesn2 knockout (cSesn2 -/- ) C57BL/6J mice were subjected to 45 minutes of ischemia followed by 2 mM metformin injection 5 minutes before 24-hour of reperfusion. Cardiac function and myocardial infarction were determined with echocardiography and 2,3,5-triphenyl tetrazolium chloride staining. Immunoblotting determines the mechanism of metformin in modulating Sesn2 to preserve mitochondrial OXPHOS components. The Seahorse XF Analyzer examined the mitochondrial respiratory functions. Results: Metformin administration can significantly improve cardiac function and reduce myocardial infarction size during I/R conditions in both young and aged wild-type C57BL/6J mice. Intriguingly, the beneficial effects of metformin administration on cardiac function and myocardial infarction were significantly blunted in the cSesn2 -/- versus Sesn2 f/f C57BL/6J mice. The immunoblotting showed metformin treatment augmented mitochondrial OXPHOS Complex II levels in young/aged wild type, and Sesn2 f/f but not cSesn2 -/- heart during I/R stress. Moreover, the mitochondrial respiration data displayed that metformin treatment improved the respiration rate of mitochondrial states 2 and 3μ in the isolated cardiomyocytes from Sens2 f/f but not from cSesn2 -/- mouse hearts under I/R stress conditions. Conclusions: Metformin can stabilize age-related Sesn2 levels in cardiomyocytes and improve cardiac function under I/R stress through maintaining mitochondrial integrity. Metformin is a potential therapeutic drug for ischemic heart disease in the elderly.
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