Acute alcohol modulates cardiac function as PI3K/Akt regulates oxidative stress.

Heavy acute alcohol exposure has been shown to negatively affect the function of many organs in the body and alter oxidative stress responses in the cardiovascular system (El-Mas and Abdel-Rahman, 2014). In particular, binge drinking is a common social form of acute alcoholic intoxication that has been shown to exert detrimental cardiovascular effects (Tonelo et al., 2013; Waszkiewicz et al., 2013). Nonetheless, reports have also demonstrated beneficial effects of low alcohol (LA) exposure (Djousse et al., 2004; Providencia, 2006; Reims et al., 2004). It has been shown that acute high alcohol (HA) exposure increases cellular oxidative stress through alterations in the AMPK and the mTOR signaling activity (Kandadi et al., 2013; Zhang et al., 2010). However, the proper mechanism(s) through which low and high levels of acute alcohol alters the cardiac function is not well deciphered. Clinically, acute heavy alcohol consumption depresses cardiac function and modifies local blood flow (Kandadi et al., 2013; Reims et al., 2004). There are many reports, which demonstrate that alcohol-induced cardiomyopathy is facilitated through the generation of oxidative stress (Kannan et al., 2004; Preedy et al., 1999). Other clinical parameters affected by acute and chronic alcohol intake include left ventricular malfunction, thinning of ventricular wall, and myocardial dysfunction (Fogle et al., 2011). LA consumption has been shown to have beneficial effects on cardiovascular function and lower risk of heart disease. Adversely, chronic HA consumption has various detrimental effects leading to alcoholic cardiomyopathy (Krenz and Korthuis, 2012). Our laboratory and others have linked the Akt pathway as a mediator of alcohol-induced translational diminishment of anti-apoptotic signals (Chen et al., 2000; Haddad et al., 2008). Akt pathway has been heavily studied with its association with induced oxidative stress (Ma and Wang, 2012), which may be linked to cardiomyopathy. The phase II antioxidant enzymes are up-regulated defending against oxidative stress (Akhtar et al., 2012). Alcohol effects on the anti-apoptotic and cell survival pathways have yet to be elucidated. The contractile cardiomyocytes are greatly affected by high doses of ethanol (EtOH) (100 to 200 mM) leading to apoptosis and later necrosis (>24 hours) (Altura et al., 1996; Doser et al., 2009; Guan et al., 2004; Kandadi et al., 2013). Apoptotic changes are mainly orchestrated through caspase 3 (Porter and Janicke, 1999). The anti-apoptotic pathway is up-regulated through PI3K/Akt via a series of phosphorylation steps when stress signals are perceived from external or internal stimuli. During acute HA exposure, there is a remarkable increase in protein phosphatase (PP2A), which leads to decreases in Akt (Chen et al., 2010;Ma et al., 2010). The sarcomere also becomes damaged interfering with its inotropic activity, which leads to cardiac muscle dysfunction (Chen et al., 2010). Thus, we hypothesize that Akt signaling pathway plays a pivotal role in mediating the detrimental versus the beneficial effects of HA versus LA exposure on the heart function, respectively.