Investigation into cellular and molecular mechanisms underlying diabetic cardiomyopathy: role of oxidative and nitrative stress therapeutic potential of multiple antioxidants

Abstract

Cardiovascular complications characterized by cardiac dysfunction are a leading cause of morbidity and mortality associated with diabetes. There are ample evidences that excess generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), largely due to hyperglycemia, causes oxidative and nitrosative stress, which further exacerbates the development and progression of diabetic cardiomyopathy. Overproduction and/or insufficient removal of these free radicals result in cardiac dysfunction, damage to cellular proteins, membrane lipids and nucleic acids. Despite overwhelming evidence on the damaging consequences of oxidative and nitrosative stress and its role in experimental diabetes, large scale clinical trials with classic antioxidants failed to demonstrate any benefit for diabetic patients with cardiovascular complications. As our understanding of the mechanisms of free radical generation evolves, it is becoming clear that rather than merely scavenging reactive radicals, a more comprehensive approach aimed at preventing the generation of these reactive species as well as scavenging may prove more beneficial. High glucose (HG) generates reactive oxygen species (ROS) as a result of glucose auto-oxidation. Since glucose oxidase catalyses the oxidation of D-glucose in vitro, we exposed H9c2 cardiac myoblast cells to high glucose (33 mM) and glucose oxidase (1.6 mU/ml) to generate ROS and/or RNS in vitro, and termed it G/GO. Using this model, we tested the hypothesis that NAC, catalase and GSH may exert a beneficial effect in preventing high-glucose mediated cardiac cell apoptosis. Our invitro studies indicate that NAC, catalase and GSH exerts a protective effect on G/GO-induced apoptosis in H9C2 cardiac muscle cells via inhibition of ROS and RNS generation and mitochondrial death pathways.