Alcoholic cardiomyopathy is a disease caused by excessive consumption of ethanol and can lead to progressive cardiac dysfunction and heart failure. Ethanol consumption is associated with increased systemic production of pro-inflammatory cytokines such as tumor necrosis factor (TNF-alpha). TNF-alpha R1 receptors (TNFR1) induces activation of the enzyme NAD(P) H oxidase with consequent increase in the production of reactive oxygen species (ROS), such as superoxide anion (O2-), which induces lipid peroxidation, protein oxidation and the activation of intracellular pathways associated with inflammation, cardiac hypertrophy and remodeling. In addition, O2- can react with nitric oxide (NO), leading to the generation of peroxynitrite (ONOO-), a molecule with a high oxidizing capacity. In the heart, NO plays an important physiological role in controlling coronary blood flow and the contractility of the cardiac muscle, and the reduced NO bioavailability is related to myocardial necrosis and heart failure. The physiological cardiac NO production is mediated by the constitutive isoforms of the enzyme NOS: endothelial NO synthase (eNOS) and neuronal NO synthase (nNOS). The TNFR1 receptor negatively modulates the activity of eNOS and its activation by TNF-alpha is associated with reduced bioavailability of NO. Although the relationship between ethanol consumption and increased systemic production of TNF-alpha is well established, there are no studies evaluating the mechanisms and the participation of this cytokine in the cardiac toxicity induced by ethanol consumption. Our hypothesis is that ethanol increases TNF-alpha production which, via TNFR1 receptors will promote NAD(P)H oxidase activation with consequent increase in ROS production and lipid peroxidation, and reduced bioavailability NO and NOS expression.
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