Conundrum of pathogenesis of diabetic cardiomyopathy: role of vascular endothelial dysfunction, reactive oxygen species, and mitochondria

Abstract

Diabetic cardiomyopathy and heart failure have been recognized as the leading causes of mortality among diabetics. Diabetic cardiomyopathy has been characterized primarily by the manifestation of left ventricular dysfunction that is independent of coronary artery disease and hypertension among the patients affected by diabetes mellitus. A complex array of contributing factors including the hypertrophy of left ventricle, alterations of metabolism, microvascular pathology, insulin resistance, fibrosis, apoptotic cell death, and oxidative stress have been implicated in the pathogenesis of diabetic cardiomyopathy. Nevertheless, the exact mechanisms underlying the pathogenesis of diabetic cardiomyopathy are yet to be established. The critical involvement of multifarious factors including the vascular endothelial dysfunction, microangiopathy, reactive oxygen species (ROS), oxidative stress, mitochondrial dysfunction has been identified in the mechanism of pathogenesis of diabetic cardiomyopathy. Although it is difficult to establish how each factor contributes to disease, the involvement of ROS and mitochondrial dysfunction are emerging as front-runners in the mechanism of pathogenesis of diabetic cardiomyopathy. This review highlights the role of vascular endothelial dysfunction, ROS, oxidative stress, and mitochondriopathy in the pathogenesis of diabetic cardiomyopathy. Furthermore, the review emphasizes that the puzzle has to be solved to firmly establish the mitochondrial and/or ROS mechanism(s) by identifying their most critical molecular players involved at both spatial and temporal levels in diabetic cardiomyopathy as targets for specific and effective pharmacological/therapeutic interventions.

Effects of dipeptidyl peptidase-4 inhibitors on cardiac and endothelial function in type 2 diabetes mellitus: A pilot study

“…17 Micro-angiography and vascular endothelial dysfunction have been identified as possible mechanisms for the pathogenesis of diabetic cardiomyopathy. 29 DPP4i affect endothelial function and have been shown to be associated with an increase in biological activity of nitric oxide.…”

Ultrastructure of the placenta in gestational diabetes mellitus

“…Thus, the trophoblasts are affected by the hyperglycemic environment with reduction of its proliferation. [16][17][18] Figure 6; the cytoplasm of both types of trophoblast is occupied by a lot of membrane-bound irregular vesicular structures (black arrows) that contain a low electron-dense material. Areas rich in glycogen granules (white forked arrows) and few mitochondria (black forked arrows) appear in the Cy cell (Cy).…”

Molecular and cellular mechanisms of glucagon-like peptide-1 receptor agonist-mediated attenuation of cardiac fibrosis

“…Previous demonstration of improvements in vascular reactivity correlating with improvements in cardiac function and attenuation of cardiac failure/fibrosis lend support to this contention. 26 While the molecular mechanisms responsible for putative therapeutic effects of improvements in vascular reactivity on cardiac fibrosis are unknown reduction in oxidative stress and the concomitant attenuation of expression of inflammatory cytokines from vascular endothelial cells is thought to contribute to this effect. 27 In an attempt to further delineate the molecular mechanisms responsible for the attenuation of cardiac fibrosis in our murine models evaluation both in vitro and in vivo of liraglutide treatment on several inflammatory and oxidative stress markers was performed.…”