Abstract
Diabetes mellitus increases the risk of heart failure independently of underlying coronary artery disease, and many believe that diabetes leads to cardiomyopathy. The underlying pathogenesis is partially understood. Several factors may contribute to the development of cardiac dysfunction in the absence of coronary artery disease in diabetes mellitus. There is growing evidence that excess generation of highly reactive free radicals, largely due to hyperglycemia, causes oxidative stress, which further exacerbates the development and progression of diabetes and its complications. Hyperglycemia-induced oxidative stress is a major risk factor for the development of micro-vascular pathogenesis in the diabetic myocardium, which results in myocardial cell death, hypertrophy, fibrosis, abnormalities of calcium homeostasis and endothelial dysfunction. Diabetes-mediated biochemical changes show cross-interaction and complex interplay culminating in the activation of several intracellular signaling molecules. Diabetic cardiomyopathy is characterized by morphologic and structural changes in the myocardium and coronary vasculature mediated by the activation of various signaling pathways. This review focuses on the oxidative stress and signaling pathways in the pathogenesis of the cardiovascular complications of diabetes, which underlie the development and progression of diabetic cardiomyopathy.
Highlights
Cardiovascular disease represents the major cause of morbidity and mortality in diabetic patients [1]
Accumulating data from experimental, pathological, epidemiological, and clinical studies have shown that diabetes mellitus results in cardiac functional and structural changes, independent of hypertension, coronary artery disease, or any other known cardiac diseases, which support the existence of diabetic cardiomyopathy [2,3,4]
We found that the phosphorylation of GSK3 and the nuclear translocation of NFATc3 were elevated in mice 28 days after STZ injection, without a significant alteration in AKT activity, suggesting that there are other possible upstream activators of GSK3 that control its signaling in the diabetic myocardium, converting the pro-apoptotic stimuli of GSK3 observed in early stages of the disease [130]
Summary
Cardiovascular disease represents the major cause of morbidity and mortality in diabetic patients [1]. Hyperglycemia-induced oxidative stress is a major risk factor for the development of micro-vascular pathogenesis in the diabetic myocardium, which results in myocardial cell death, hypertrophy, fibrosis, abnormalities of calcium homeostasis, and endothelial dysfunction [16,17,18]. Diabetic mice treated with insulin showed reduced elevation of blood glucose levels and inhibition of myocardial apoptosis on day-3 after STZ treatment [79].
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