Interplay of oxidative, nitrosative/nitrative stress, inflammation, cell death and autophagy in diabetic cardiomyopathy

Abstract

Diabetes is a recognized risk factor for cardiovascular diseases and heart failure. Diabetic cardiovascular dysfunction also underscores the development of diabetic retinopathy, nephropathy and neuropathy. Despite the broad availability of antidiabetic therapy, glycemic control still remains a major challenge in the management of diabetic patients. Hyperglycemia triggers formation of advanced glycosylation end products (AGEs), activates protein kinase C, enhances polyol pathway, glucose autoxidation, which coupled with elevated levels of free fatty acids, and leptin have been implicated in increased generation of superoxide anion by mitochondria, NADPH oxidases and xanthine oxidoreductase in diabetic vasculature and myocardium. Superoxide anion interacts with nitric oxide forming the potent toxin peroxynitrite via diffusion limited reaction, which in concert with other oxidants triggers activation of stress kinases, endoplasmic reticulum stress, mitochondrial and poly(ADP-ribose) polymerase 1-dependent cell death, dysregulates autophagy/mitophagy, inactivates key proteins involved in myocardial calcium handling/contractility and antioxidant defense, activates matrix metalloproteinases and redox-dependent pro-inflammatory transcription factors (e.g. nuclear factor kappaB) promoting inflammation, AGEs formation, eventually culminating in myocardial dysfunction, remodeling and heart failure. Understanding the complex interplay of oxidative/nitrosative stress with pro-inflammatory, metabolic and cell death pathways is critical to devise novel targeted therapies for diabetic cardiomyopathy, which will be overviewed in this brief synopsis. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.

Keywords: Autophagy; Diabetic cardiomyopathy; Oxidative stress; Protein oxidation.

Figure 1. Interplay of hyperglycemia and peripheral metabolism in cardiometabolic syndrome in mediating diabetic cardiovascular complications

Hyperglycemia may indirectly (via its metabolic consequences) or directly enhance diabetes-associated inflammation and ROS generation, promoting tissue injury and the development of diabetic cardiovascular and other complications. AT II rec, angiotensin II receptor type 1; CNS, central nervous system; PMNs, polymorphonuclear leukocytes; XO, xanthine oxidase.

Figure 2. Interplay of oxidative and nitrosative/nitrative stress with cell death pathways in diabetic cardiomyopathy

Hyperglycemia via activation of various pathways shown in the large yellow box increased superoxide anion (O₂^•−) production in cardiovascular cell types. NO and superoxide (O₂^•−) rapidly react to form peroxynitrite (ONOO⁻) which induces cell injury via enhanced lipid peroxidation, inactivation of enzymes and other proteins by oxidation and nitration, and also activation of stress signaling, matrix metalloproteinases (MMPs) among others. Peroxynitrite also triggers the release of proapoptotic factors such as cytochrome c and apoptosis-inducing factor (AIF) from the mitochondria, which mediate caspase-dependent and -independent apoptotic cell demise pathways. Autophagy may be beneficial in diabetic cardiomyopathy in removal of injured cells, but additional support is required to prove its exact role. Peroxynitrite, in concert with other reactive oxidants, causes stand breaks in DNA, activating the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1). Mild damage of DNA activates the DNA repair machinery, but once excessive oxidative/nitrosative stress-induced DNA damage occurs, like in diabetes, overactivated PARP initiates an energy-consuming cycle by transferring ADP-ribose units from nicotinamide adenine dinucleotide (NAD⁺) to nuclear proteins, resulting in rapid depletion of the intracellular NAD⁺ and ATP pools, slowing the rate of glycolysis and mitochondrial respiration, eventually leading to cellular dysfunction and demise. Poly(ADP-ribose) glycohydrolase (PARG) degrades poly(ADP-ribose) (PAR) polymers, generating free PAR polymer and ADP-ribose. Overactivated PARP also facilitates the activation of NFkB and expression of a variety of pro-inflammatory genes leading to increased inflammation and associated oxidative stress, thus facilitating the progression of cardiovascular dysfunction and heart failure. Via attenuation of the cellular NAD+ levels PARP activation may also promote metabolic dysfunction via decreased activity of SIRT-1 in various tissues. In addition to these adverse consequences the NO bioavailability and signaling is also impaired in diabetic hearts promoting impaired vasorelaxation and enhanced atherogenesis eventually facilitating increased cardiovascular inflammation, and lipid deposition in vessels and myocardium, functional ischemia and enhanced cardiac injury.

Figure 3. Progression of diabetic cardiomyopathy: role of oxidative/nitrosative stress, inflammation, cell death and remodeling

The mechanisms leading to diabetic cardiomyopathy and failure are complex. Eventually the pathological alterations will result in mismatch between the load applied to the heart and the energy needed for contraction, leading to mechanoenergic uncoupling. After initial insults (episodes of hyperglycemia), secondary mediators such as angiotensin II (AII), norepinephrine (NE), endothelin (ET), proinflammatory cytokines [e.g., tumor necrosis factor-α (TNF-α) and interleukin 6 and IL1β (IL-6 and IL1β), in concert with oxidative stress and peroxynitrite, activate downstream effectors (e.g., PARP-1 or MMPs)], act directly on the myocardium or indirectly via changes in hemodynamic loading conditions to cause endothelial and myocardial dysfunction, cardiac and vascular remodeling with hypertrophy, fibrosis, cardiac dilation, and myocardial necrosis, leading eventually to heart failure. The adverse remodeling and increased peripheral resistance further aggravate heart failure. MMPs, matrix metalloproteinases; PARP-1, poly(ADP-ribose) polymerase.