Autophagy is a highly conservative intracellular bulk degrad

Autophagy is a highly conservative intracellular bulk degradation process including three major forms namely microautophagy, chaperone-mediated autophagy and macroautophagy. A large number of evidence has depicted a pivotal role for autophagy in the maintenance of cardiac geometry and contractile function. Impaired autophagy is present in various forms of heart diseases including diabetes, hypertension, stroke, ischemia-reperfusion injury and myocardial infarction (MI). Long-term alcohol intake has been known to dampen cardiac protein expression and synthesis and speed up protein degradation [12,13], suggesting a role for protein catabolism and autophagy in alcoholic heart diseases. Histopathologic examination also revealed contractile protein loss, fragmentation, and disarray in hearts from patients with alcoholic cardiomyopathy [52,53]. Using proteomic analysis, Fogle and colleagues revealed that 16-week chronic alcohol intake triggered a robust decrease in a number of myocardial proteins including myofibrillar proteins (e.g., myosin and actin), mitochondrial proteins (e.g., electron transport proteins and mitochondrial dehydrogenases), glycolytic proteins (e.g., glycogen phosphorylase, alpha enolase), fatty allopurinol zyloprim metabolism proteins (e.g., long-chain fatty acid acyl-CoA ligase and fatty acid transport protein), and antioxidant proteins (e.g., antioxidant protein 2 and glutathione transferase 5) [54]. Accelerated protein degradation may be due to changes in protein quality control machineries including ubiquitin-proteasome system (UPS) [e.g., ubiquitin E3 ligases such as atrogin-1 and muscle RING Finger 1 (MuRF1)] and autophagy. Chronic alcohol intake was shown to upregulate myocardial atrogin-1 and MuRF1 levels in rats [55]. Alcohol intake-induced suppression of myocardial protein synthesis is believed to be mediated in part by reduced phosphorylation of mammalian target of rapamycin (mTOR) [56], a kinase critical for the regulation of cell growth, proliferation, motility, protein synthesis, and transcription [56]. Compromised mTOR activity has been confirmed in a number of pathological conditions involving muscle atrophy, reduced myocardial protein synthesis, and ventricular dilation [57]. Interestingly, levels of autophagy markers including LC3B and Atg7 were found to be elevated in chronically-alcohol challenged rat hearts [55], in conjunction with suppressed mTOR activity, a pivotal negative regulator of autophagy. Evidence from our group and others also noted elevated autophagy protein markers (enhanced LC3B, Beclin1, Atg3, and Atg7 as well as decreased mTOR phosphorylation) in mouse hearts in association with cardiac remodeling and contractile dysfunction (such as myocardial interstitial fibrosis, decreased left ventricular wall and septal thickness, enlarged end systolic and diastolic diameters, decreased fractional shortening and cell shortening) in mice following a 12-week Liber-DeCarli alcohol intake [40,58]. Similar observation was noted in autophagosome accumulation following an 8-week chronic alcohol intake [59]. Likewise, acute or binge drinking (3 g/kg/d, for 3 days) also elicited overt unfavorable changes in cardiac geometry and function as evidenced by enlarged ventricular end systolic and diastolic diameters, myocardial apoptosis, ROS accumulation, decreased cardiomyocyte shortening and intracellular Ca2+ rise, prolonged relengthening and intracellular Ca2+ decay in association with elevated autophagy markers Beclin-1, Atg7 and LC3B II [50,51,60,61]. These findings collectively suggest a role for autophagy in the pathogenesis of alcoholic cardiomyopathy. As an important process to govern organismal survival in stress and nutrient deprivation, autophagy is found upregulated in a number of cardiac pathological conditions including septic cardiac anomalies, heart failure, cardiomyopathy, and cardiac hypertrophy [62,63]. Nonetheless, the mechanism of action behind autophagy and its signaling regulatory cascades remains elusive in alcoholic cardiomyopathy. Here we will discuss the potential contributing mechanisms of changes in autophagy in alcoholic cardiomyopathy.