Mitochondrial ROS Formation in the Pathogenesis of Diabetic Cardiomyopathy

Abstract

Diabetic cardiomyopathy is a result of diabetes-induced changes in the structure and function of the heart. Hyperglycemia affects multiple pathways in the diabetic heart, but excessive reactive oxygen species (ROS) generation and oxidative stress represent common denominators associated with adverse tissue remodeling. Indeed, key processes underlying cardiac remodeling in diabetes are redox sensitive, including inflammation, organelle dysfunction, alteration in ion homeostasis, cardiomyocyte hypertrophy, apoptosis, fibrosis, and contractile dysfunction. Extensive experimental evidence supports the involvement of mitochondrial ROS formation in the alterations characterizing the diabetic heart. In this review we will outline the central role of mitochondrial ROS and alterations in the redox status contributing to the development of diabetic cardiomyopathy. We will discuss the role of different sources of ROS involved in this process, with a specific emphasis on mitochondrial ROS producing enzymes within cardiomyocytes. Finally, the therapeutic potential of pharmacological inhibitors of ROS sources within the mitochondria will be discussed.

NLRP3 as Putative Marker of Ipilimumab-Induced Cardiotoxicity in the Presence of Hyperglycemia in Estrogen-Responsive and Triple-Negative Breast Cancer Cells

“…Several signaling pathways could be modified during high glucose, for example the increase of inoxidative stress and the overproduction of advanced glycation end products (AGEs) associated with pro-inflammatory cytokines leading to cellular death or chemo-resistance [ 36 , 37 ]. However, the signaling pathways directly triggered by hyperglycemia appear to have a pivotal role in diabetic complications due to the production of reactive oxygen species (ROS) and lipid peroxides [ 38 ]. However, surprisingly, in co-cultures of breast cancer cells and hPBMCs, low glucose increases ROS production ( Figure 3 ) compared to high glucose; these effects could be explained by the production of ROS following the cytotoxic effect of hPBMCs against cancer cells [ 39 ]; T-cell mediated cytotoxicity involves granzyme B and other pro-apoptotic and pro-oxidizing factors.…”

Interrelation between ROS and Ca2+ in aging and age-related diseases

“…Notably, cardiac mitochondria from diabetic patients were found to exhibit elevated hydrogen peroxide levels, impaired mitochondrial respiratory capacity and increased levels of oxidized proteins. This might lead to compromised ATP generation and increased propensity to mPTP opening [ 140 ]. Also NOX enzymes, including Ca 2+ sensitive NOX1, NOX2 and NOX5, are a key source of ROS in the diabetic environment and able to enhance diabetic complications such as nephropathy, retinopathy and cardiomyopathy [ 141 ].…”

Oxidative Stress and Vascular Dysfunction in the Retina: Therapeutic Strategies

“…However, the ETC is not entirely efficient, so there is a basal level of electron leak under even the most optimal conditions. The inadvertent leakage of electrons and their reaction with molecular oxygen are major contributors to the production of cellular reactive oxygen species (ROS) [ 1 , 2 ]. Free radicals are atoms or molecules, which have one or more unpaired electrons in their outermost orbital shell, which makes them strongly reactive and thus capable of undergoing chain reactions responsible for the oxidative damage of cells and tissues [ 3 ].…”