Abstract 11766: Sestrin2 Promotes LKB1-Mediated AMPK Activation in the Ischemic Heart
Background: The molecular mechanism behind the regulation of AMP-activated protein kinase (AMPK) activity in the ischemic heart remains incompletely understood and is elemental for the development of new therapeutic strategies. Recent evidence implicates an important role of Sestrin2 in the activation of the AMPK signaling pathway and we therefore hypothesize that Sestrin2 plays an influential role during myocardial ischemia in order to promote AMPK activation and subsequent cardioprotection.
Methods and Results: We isolated adult cardiomyocytes from mouse hearts and for the first time demonstrated that Sestrin2 protein is expressed in the cardiomyocytes. Interestingly, Sestrin2 protein levels were found to significantly accumulate in the heart during ischemic versus basal conditions (p<0.05). Male wild-type (WT) and Sestrin2 KO mice (all C57BL/6 background) were used to characterize the role of Sestrin2 in the heart in response to ischemic insults. Cardiac phenotype analysis using a pressure-volume loop catheter indicated no significant difference in left ventricular function between WT and Sestrin2 KO mice. When WT and Sestrin2 KO mice were subjected to in vivo ischemia/reperfusion (I/R), myocardial infarct size was significantly greater in Sestrin2 KO versus WT hearts (p<0.05). Langendorff perfused hearts also showed exacerbated post-ischemic contractile function in Sestrin2 KO versus WT hearts (p<0.05). Intriguingly, ischemic AMPK activation was significantly reduced in Sestrin2 KO versus WT hearts (p<0.01). Immunoprecipitation of Sestrin2 from WT hearts demonstrated a strong association with AMPK. Importantly, the Sestrin2 immune-complexes revealed a striking association with LKB1, one upstream kinase of AMPK, during ischemia in a time-dependent manner. Immunoprecipitation of cardiac LKB1 further confirmed the interaction between AMPK and LKB1 during ischemia in the WT but not in the Sestrin2 KO hearts, even though the LKB1 protein levels are the same in both WT and Sestrin2 KO hearts.
Conclusions: Sestrin2 plays an important role in cardioprotection against I/R injury via modulating cardiac AMPK signaling pathway. Sestrin2 acts as an LKB1-AMPK scaffold to initiate cardiac AMPK activation in response to ischemic stress. .
- © 2012 by American Heart Association, Inc.