Abstract
Introduction: A novel stress-inducible protein, Sestrin2, declines in the heart with aging. AMP-activated Protein Kinase (AMPK) has emerged as a pertinent stress-activated kinase shown to have cardioprotective capabilities against myocardial ischemic injury. We identified the interaction between Sestrin2 and AMPK in the ischemic heart. Hypothesis: The ischemic AMPK activation modulated by Sestrin2-AMPK complex in the heart is impaired in aging that sensitizes heart to ischemic insults. Methods: C57BL/6 young mice (4-6 months), middle age mice (10-12 months) and aged mice (24-26 months) were subjected to left anterior descending coronary artery occlusion for in vivo regional ischemia. The ex vivo working heart system was used for measuring substrate metabolism. Results: The protein level of Sestrin2 in the hearts were gradually decreased with aging. Intriguingly, ischemic AMPK activation was blunted in the aged hearts as compared with young hearts (p<0.05), the AMPK downstream glucose uptake and the rate of glucose oxidation were significantly impaired in the aged hearts during ischemia and reperfusion (I/R) (p<0.05 vs. young hearts). The myocardial infarction size was larger in the aged hearts (p<0.05 vs. young hearts). The immunoprecipitation with Sestrin2 antibody revealed that cardiac Sestrin2 forms a complex with AMPK and upstream LKB1 during ischemia, intriguingly, the binding affinity between Sestrin2 and AMPK upstream LKB1 is impaired in the aged hearts during ischemia (p<0.05 vs. young hearts). Furthermore, Sestrin2 knock out hearts demonstrate a similar cardiac phenotype and response to ischemic stress as the wild type aged hearts, i.e. impaired ischemic AMPK activation and higher sensitivity to I/R-induced injury. Adeno-associated virus 1 (AAV1)-Sestrin2 were delivered into the aged hearts via a coronary delivery approach significantly rescued the protein level of Sestrin2 and the ischemic tolerance of aged hearts. Conclusions: Sestrin2 is a scaffold protein that mediates AMPK activation in the ischemic myocardium via an interaction with AMPK upstream LKB1. The decreased Sestrin2 levels in aging lead to a blunted ischemic AMPK activation, alterations in substrate metabolism and an increased sensitivity to ischemic insults.
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