Sirt1 ameliorated cardiac autophagic flux blockage via Prx2 during myocardial ischemia/reperfusion injury

Abstract

Abstract Cardiac autophagic flux is impaired in myocardial ischemia-reperfusion (MI/R), leading to intracellular accumulation of autophagosomes and harmful substances, which further aggravates myocardial injury. Notably, Sirt1 has been proved to play an important role in regulating autophagic flux in cardiomyocytes under starvation. However, mechanisms for Sirt1 on MI/R induced autophagic flux impairment remain to be illuminated. Prx2, one member of peroxidoredoxins participating in the regulation of autophagy, is intimately connected to cell survival in MI/R. Therefore, it was necessary to verify the critical role of Sirt1 and Prx2 in the regulation of autophagic flux in MI/R. Hydrogen peroxide (H2O2) cardiomyocytes and MI/R mice were used to assess the role of Sirt1 and Prx2 in cardiac autophagic flux. We found that cardioprotective effect of Sirt1 was dependent on its cardiac autophagic flux regulation in vitro by Chloroquine (CQ), a specific inhibitor of autophagic flux. Adenovirus induced Sirt1 overexpression could promote autophagosome-lysosome fusion via activating Rab7 and Lamp2 leading to the enhanced autophagic flux against MI/R injury in vitro and in vivo. Additionally, knockdown of Prx2 aggravated autophagic flux arrest by decreasing expressions of autolysosome fusion proteins. Notably, such beneficial actions of Sirt1 were blocked by the Prx2 silence. Mechanically, our data uncovered a clue, for the first time that acetylation of Prx2 was significantly decreased by Sirt1 overexpression in cardiomyocytes or in whole hearts under physiological or pathological status. These findings have offered a direct proof and new perspective of post-translational modification in the understanding of autophagic flux and MI/R treatment.