Targeting Autophagy for the Therapeutic Application of Histone Deacetylase (HDAC) 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 the advent of therapeutic breakthroughs over the past decades such as percutaneous coronary intervention, anti-platelet, anti-thrombotic 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 that 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 as well as build-up of reactive oxygen species (ROS), uses glycolysis as the primary source for metabolic energy. As a consequence, metabolic acidosis, hyperkalemia and Ca2+-overload develop in cardiomyocytes following coronary artery occlusion, leading not only to cardiomyocyte apoptosis during the acute phase, but also delayed adverse myocardial remodeling that further compromises cardiac function 2. Therefore, limiting I/R-induced myocardial ROS accumulation and apoptosis benefits both acute and long term survival and quality of life. Although the mechanism(s) 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 highlighting 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 the long-term post-infarction cardiac remodeling 1, 3.
- Received December 24, 2013.
- Accepted December 30, 2013.