Oxidative stress and diabetic complications

Abstract

Oxidative stress plays a pivotal role in the development of diabetes complications, both microvascular and cardiovascular. The metabolic abnormalities of diabetes cause mitochondrial superoxide overproduction in endothelial cells of both large and small vessels, as well as in the myocardium. This increased superoxide production causes the activation of 5 major pathways involved in the pathogenesis of complications: polyol pathway flux, increased formation of AGEs (advanced glycation end products), increased expression of the receptor for AGEs and its activating ligands, activation of protein kinase C isoforms, and overactivity of the hexosamine pathway. It also directly inactivates 2 critical antiatherosclerotic enzymes, endothelial nitric oxide synthase and prostacyclin synthase. Through these pathways, increased intracellular reactive oxygen species (ROS) cause defective angiogenesis in response to ischemia, activate a number of proinflammatory pathways, and cause long-lasting epigenetic changes that drive persistent expression of proinflammatory genes after glycemia is normalized ("hyperglycemic memory"). Atherosclerosis and cardiomyopathy in type 2 diabetes are caused in part by pathway-selective insulin resistance, which increases mitochondrial ROS production from free fatty acids and by inactivation of antiatherosclerosis enzymes by ROS. Overexpression of superoxide dismutase in transgenic diabetic mice prevents diabetic retinopathy, nephropathy, and cardiomyopathy. The aim of this review is to highlight advances in understanding the role of metabolite-generated ROS in the development of diabetic complications.

Figures

Fig.1

General features of hyperglycemia-induced tissue damage. Reprinted with permission from the American Diabetes Association via the Copyright Clearance Center from Brownlee [4].

Fig 2

Model of ischemia-induced neovascularization in normal and high glucose. A. In the presence of normal glucose concentration, ischemia-stabilized HIF1α forms heterodimers with ARNT which bind the coactivator p300. This complex binds to the hypoxia response element (HRE) and activates expression of genes required for neovascularization. B. High glucose-induced methylglyoxal (MG) modifies HIF1α and p300, inhibiting complex binding to the HREs of genes required for neovascularization (Data from Thangarajah et al. [34] and Ceradini, et al.[35]) (Illustration Credit: Ben Smith/Cosmocyte)

Fig.3

Production of ROS by the mitochondrial electron transport chain. In cultured endothelial cells the electron donors NADH and FADH2 are generated by the oxidation of glucose-derived pyruvate. The flow of the donated electrons (e−) through the electron-transport chain in the inner mitochondrial membrane pumps H+ ions into the intermembrane space. When the voltage gradient is high due to increased flux of electron donors, more superoxide is generated. H+ ions can pass back across the inner membrane along their concentration gradient, either via ATP synthase (to produce ATP) or via uncoupling proteins (UCP), which dissipate the energy of the proton gradient as heat. ADP, adenosine diphosphate; Cyt c, cytochrome c; FAD, flavin adenine dinucleotide; NAD, nicotinamide adenine dinucleotide (Adapted From Brownlee [4]).

Fig. 4

Schematic showing elements of the unifying mechanism of hyperglycemia-induced cellular damage (Adapted form Brownlee [4]).

Fig. 5

Hyperglycemia-induced activating modifications of histone 3 lysine 4 and derepressing modifications of histone 3 lysine 9 at the NFκB p65 proximal promoter (Data from El-Osta et al. [105] and Brasacchio et al. [106])

Fig.6

Role of insulin resistance and free fatty acids in macrovascular endothelial cell ROS formation and atherogenesis (Data form Du X, et al [116]).