Targeting Autophagy for the Therapeutic Application of Histone Deacetylase Inhibitors in Ischemia/Reperfusion Heart Injury

Abstract

Editorial 1088I schemic heart disease is a leading cause of morbidity and mortality in the United States and other parts of the world. Despite therapeutic breakthroughs over the past decades such as percutaneous coronary intervention, antiplatelet and antithrombotic therapies, and angioplasty, the prevalence of ischemic heart diseases remains extremely high and constitutes a devastating factor for heart failure.1,2 Among various therapeutic strategies for ischemic heart disease, enormous efforts have been made to limit ischemia/reperfusion (I/R) injury, which occurs when the ischemic myocardium is reperfused with oxygen and substrate-rich blood, which paradoxically worsens heart function.2 Ischemic myocardium, with nutrient and oxygen deprivation and buildup of reactive oxygen species (ROS), uses glycolysis as the primary source of metabolic energy. As a consequence, metabolic acidosis, hyperkalemia, and Ca 2+ overload develop in cardiomyocytes after coronary artery occlusion, leading not only to cardiomyocyte apoptosis during the acute phase but also to delayed adverse myocardial remodeling, which further compromises cardiac function.2 Therefore, limiting I/R-induced myocardial ROS accumulation and apoptosis benefits both short-and long-term survival and quality of life. Although the mechanism responsible for I/R-induced cardiac abnormalities has been focused largely on necrosis and type I (apoptotic) programmed cell death, 2 an intriguing and provocative paradigm has emerged recently that highlights a unique role for dysregulated macroautophagy (hereafter referred to as autophagy) in the heart that may render cardiomyocytes more prone to I/R injury and long-term postinfarction cardiac remodeling.1,3 It has been perceived that autophagy induced by ischemic preconditioning is essential for cardioprotection. To this end, new and innovative strategies to maintain or restore myocardial autophagy homeostasis and its attendant, cardiomyocyte survival, have been the subject of intensive investigation. Article see p 1139The Janus-Faced Role of Autophagy Induction in I/R Injury Autophagy is a tightly regulated, lysosome-dependent catabolic process responsible for turnover of long-lived proteins and intracellular structures that are damaged or malfunctioning. 4,5 The evolutionally conserved bulk degradation process is turned on when cells experience stress, including nutrient and energy deprivation. The autophagic pathway consists of 4 distinct but consecutive steps: initiation, formation of autophagosomes (ie, the double-membrane structures that encircle cargo of damaged cytosolic constituents), generation of autophagolysosomes via docking and fusion with lysosomes, and final degradation of sequestered cargo. Sequestration of cytoplasmic cargo such as long-lived proteins, damaged organelles, and protein aggregates into the double-membrane vesicle autophagosomes occurs before fusion with lysosomes for degradation of its contents by acidic hydrolases. Although physiological levels of autophagy are essential for mitochondr...

MicroRNA-374 Exerts Protective Effects by Inhibiting SP1 Through Activating the PI3K/Akt Pathway in Rat Models of Myocardial Ischemia-Reperfusion After Sevoflurane Preconditioning

“…Occurring at the time of reperfusion of ischemic myocardium with oxygen and substrate-rich blood, reperfusion could sometimes paradoxically deteriorate heart function [2]. Anesthetics such as sevoflurane and isoflurane are reported to be valid therapeutic drugs for I/R injury [3].…”

Inhibition of microRNA-101 attenuates hypoxia/reoxygenation-induced apoptosis through induction of autophagy in H9c2 cardiomyocytes

“…As low levels of autophagy during ischemia and early reperfusion protect against cell death, it was suggested that spontaneous upregulation of autophagy may prevent excessive apoptosis of cardiomyocytes in response to H/R. Numerous studies have also demonstrated that autophagy is a beneficial response to ischemia/reperfusion (I/R) (21)(22)(23)(24). For example, increased autophagy was demonstrated to correlate with the functional recovery of the myocardium following I/R, and cardiac myocytes exhibiting enhanced levels of autophagy were found to be negative for apoptosis (25,26).…”

The role of mitochondria in cardiac development and protection

“…Hypoxia and oxidative damage have been shown to induce autophagy in cardiomyocytes [33] and are induced via the mitochondrially regulated AMPK-ULK1 signaling pathway [23]. Interestingly, autophagy seems to have a protective role in mild ischemia but can develop to be detrimental after ischemia-reperfusion [43,44]. The latter could result from the overload of autophagosome processing as well as delayed clearance of damaged organelles, resulting in increased ROS generation and cell death following MPTP opening.…”