Autophagy-dependent cardioprotection in ischemia/reperfusion injury

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): Rapid restoration of blood flow to the ischemic heart is vital in acute coronary syndromes. However, reperfusion also contributes significantly to myocardial infarct size(1). Currently, there are no clinical therapies targeting reperfusion injury Elucidation of mechanisms of reperfusion injury -- with an eye toward clinical translation -- is urgently needed. Inhibition of class 1 histone deacetylases (HDACs), specifically at the time of reperfusion, confers cardioprotection in multiple animal models of ischemia/reperfusion (I/R) injury(2, 3). Autophagy is critical in the response to I/R injury(3). We have demonstrated that HDAC inhibition promotes cardiomyocyte autophagy, which is critical to the robust cardioprotective effects we observe(3). Also, appropriate mitochondrial quality control is critical to cardioprotection during I/R(4, 5). Here, we will define mechanisms whereby cardiomyocyte autophagy protects against I/R injury. We propose to manipulate autophagy using two strategies: a) HDAC inhibition, and b) a cell-permeable peptide (Tat-Beclin), a strong autophagy activator(6). The former approach is imminently translatable to the clinical context. The latter approach allows us to isolate specifically the contribution of activated autophagy, parsing it from other effects of HDAC inhibition. Also, we will define mechanisms whereby activated autophagy is protective, focusing on excessive ROS production by defective mitochondria escaping autophagic elimination. We hypothesize that Tat-Beclin treatment will promote autophagy and confer cardioprotection to reperfusion-injured myocardium. We also hypothesize that induction of autophagy either with HDAC inhibition or Tat-Beclin will lead to a decrease in ROS production during reperfusion in the border zone resulting in increased cardiomyocyte survival. Aim 1: Determine whether Tat-Beclin induces autophagy and whether it is cardioprotective in I/R- stressed cardiomyocytes in vitro. Aim 2: Determine whether Tat-Beclin is cardioprotective in an in vivo cardiac I/R injury model and whether autophagy is essential for the cardioprotection. Aim 3: Determine whether therapeutically up-regulated cardiomyocyte autophagy preserves mitochondrial function and reduces ROS production. This proposal is timely, mechanistic, novel, and holds great potential to reduce morbidity and mortality in ischemic heart disease. Tat-Beclin, a selective autophagy inducer, is a powerful way to extend our understanding of autophagy-dependent cardioprotection in I/R injury. Further, we will explore cardioprotective reperfusion targets in the autophagic pathway, such as ROS regulation. As Tat-Beclin is a potential therapeutic agent, this is a uniquely translational strategy with potential for clinical impact. Finally, this research serves as a critical platform for me to complete my training as a physician-scientist.