Autophagy in Myocardial Ischemia/Reperfusion

San Diego State University, San Diego CA

Investigators

Linked publications & trials

Abstract

Autophagy is a physiologic process whereby cytoplasmic components including organelles are engulfed by[unreadable] a double membrane structure and targeted for destruction via lysosomes. Although it is a constitutive[unreadable] process in the myocardium, the level of autophagy is upregulated in response to ischemia/reperfusion[unreadable] (I/R) and possibly other pathophysiologic processes. Autophagy has been implicated in cell death and[unreadable] cytoprotection in different contexts. We hypothesize that autophagy is a protective response in the[unreadable] reperfused heart. We will establish the role of autophagy in the isolated perfused heart subjected to global[unreadable] I/R. and in cultured adult cardiomvocvtes subjected to simulated I/R. utilizing the fluorescent reporter of[unreadable] autophagy, LC3-GFP, and will develop novel reagents including a fluorescent reporter delivered by protein[unreadable] transduction and a cardiac-specific LC3-mCherry transgenic mouse. Mitochondria are important targets of[unreadable] autophagy in the heart, and we hypothesize that elimination of individual damaged or dysfunctional[unreadable] mitochondria may avert programmed cell death by preventing the propagation of reactive oxygen species[unreadable] (ROS) and pro-apoptotic signals to the remainder of the mitochondrial population. We propose to monitor[unreadable] ROS-induced ROS release (RIRR) in adult cardiomvocvtes and to assess whether autophagy can function to[unreadable] limit RIRR. using live-cell imaging (Core B). Because autophagy is closely tied to the metabolic state of the[unreadable] cell, we will examine its regulation by Akt, mTOR, and AMP-dependent kinase. In conjunction with Projects[unreadable] 1, 2, and 3, we will examine whether cytoprotective pathways (Akt, hexokinase, Pim-1, alphaB-crvstallin)[unreadable] stabilize mitochondria directly or through upregulation of autophagy. Autophagy is suppressed during[unreadable] hypertrophy; we will test the hypothesis that the resulting accumulation of damaged mitochondria may[unreadable] contribute to the development of failure after thoracic aortic constriction (Core C). In conjunction with Project[unreadable] 5, we will examine whether autophagy contributes to healthy or pathologic remodeling after permanent[unreadable] ischemia, and will determine the role of sphingosine-1-phosphate signaling in the regulation of autophagy.[unreadable] These studies will delineate the role of autophagy in cardiac health and disease.