Abstract 12099: Activated Notch1 Interacting With LKB1 Reduces Myocardial Ischemic Injury via Modulating AMPK Signaling Pathway

Abstract

Introduction: The activation of the intrinsic AMP-activated protein kinase (AMPK) pathway plays an important role in the myocardial response to ischemia, pressure overload, and heart failure. The Notch1 signaling in the adult myocardium is activated transiently in response to myocardial injury, and it has implicated that Notch1 signaling may contribute to cardiac repair. However, the role of Notch1 signaling in myocardial infarction remain uncertain. Hypothesis: The cardioprotective AMPK signaling pathway could mediate the beneficial effects of Notch1 signaling cascade during myocardial infarction. Methods: C57BL/6J male mouse hearts were subjected in vivo to left anterior descending coronary artery ligation for 5 min, 20 min, 24 hr, 1 week and 2 weeks. Mice were treated with dibenzazepine (DBZ), a new Notch γ-secretase inhibitor (5 μmol/kg/day, i.p.) and the vehicle groups were treated with saline. Ischemic heart tissues were harvested for protein, mRNA expression and histologic analysis. Results: The Notch1 signaling was significantly activated during myocardial ischemia in vivo (p<0.05 vs. sham group). Interestingly, in the ex vivo heart perfusion system, systemic administration of DBZ to hearts led to significantly increase of myocardial infarct size and apoptosis caused by myocardial ischemia (p<0.05 vs. vehicle group). The immunoblotting results demonstrated that DBZ treatment significantly inhibited the AMPK activation by myocardial ischemia (p<0.05 vs. ischemia alone). Further immunoprecipitation experimental data showed that activated Notch1 strongly interacts with one AMPK upstream kinase, LKB1, to form a complex that modulates cardiac AMPK activation during myocardial ischemia. Moreover, the inhibition of Notch1 by DBZ impaired AMPK activation that significantly increased inflammation response such as activation of c-Jun N-terminal protein kinase (JNK) and NF-κB signaling during myocardial ischemia. Conclusions: The activated Notch1 signaling interacts with LKB1 to trigger the activation of cardioprotective AMPK signaling during myocardial ischemia. The Notch1-LKB1-AMPK signaling cascade could be a potential pharmacologic mimic for cardioprotection of ischemic heart disease.