Abstract
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. It is hypothesized that the ischemic AMPK activation modulated by Sestrin2‐AMPK complex in the heart is impaired in aging that sensitizes heart to ischemic insults.MethodsC57BL/6 young mice (3–4 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. 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 (AAV)‐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. Therefore, 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.Support or Funding InformationADA 1‐14‐BS‐131, NIHR21AG044820
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