Targeting autophagy for the therapeutic application of histone deacetylase inhibitors in ischemia/reperfusion heart injury.

I 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 anti-thrombotic therapies, and angioplasty, the prevalence of isch-emic heart diseases remains extremely high and constitutes a devastating factor for heart failure. 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. 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. Autophagy is a tightly regulated, lysosome-dependent cata-bolic process responsible for turnover of long-lived proteins and intracellular structures that are damaged or malfunctioning. 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 autoph-agy are essential for mitochondrial function, cell survival, and cell …