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

Ischemic 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 Ca2+ 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 1139 Autophagy is a tightly regulated, lysosome-dependent catabolic process responsible for turnover of long-lived proteins and intracellular …