Sestrin2 is cardioprotective against ischemia/reperfusion injury by promoting LKB1‐mediated AMPK activation

The mechanism of AMP‐activated protein kinase (AMPK) activation in the ischemic heart remains poorly understood. Recent evidence implicates the role of Sestrin2 (Sesn2) in the AMPK signaling pathway and we hypothesize that Sesn2 plays an influential role during myocardial ischemia in order to promote AMPK activation. Sesn2 protein was found to be expressed in adult cardiomyocytes. Interestingly, Sesn2 was found to accumulate in the heart during ischemic conditions. Cardiac phenotype analysis of WT and Sesn2 KO mice were not significantly different. When subjected to in vivo ischemia/reperfusion (I/R), myocardial infarction was significantly greater in Sesn2 KO versus WT hearts. Similarly, Langendorff perfused hearts indicated exacerbated cardiac function after I/R injury in Sesn2 KO versus WT as evidenced by decreased LVDP, dP/dt, and rate‐pressure products. Moreover, ischemic AMPK activation was reduced in Sesn2 KO hearts. Immunoprecipitation of Sesn2 demonstrated an association with AMPK. Importantly, immunoprecipitation of LKB1 from WT hearts demonstrated AMPK association during ischemia while LKB1‐AMPK interaction in Sesn2 KO hearts was nearly abolished. The results demonstrate an important cardioprotective role of Sesn2 against I/R injury by acting as a LKB1‐AMPK scaffold.