Role of nitrosative stress and peroxynitrite in the pathogenesis of diabetic complications. Emerging new therapeutical strategies

Abstract

Macro- and microvascular disease are the most common causes of morbidity and mortality in patients with diabetes mellitus. Diabetic cardiovascular dysfunction represents a problem of great clinical importance underlying the development of various severe complications including retinopathy, nephropathy, neuropathy and increase the risk of stroke, hypertension and myocardial infarction. Hyperglycemic episodes, which complicate even well-controlled cases of diabetes, are closely associated with increased oxidative and nitrosative stress, which can trigger the development of diabetic complications. Hyperglycemia stimulates the production of advanced glycosylated end products, activates protein kinase C, and enhances the polyol pathway leading to increased superoxide anion formation. Superoxide anion interacts with nitric oxide, forming the potent cytotoxin peroxynitrite, which attacks various biomolecules in the vascular endothelium, vascular smooth muscle and myocardium, leading to cardiovascular dysfunction. The pathogenetic role of nitrosative stress and peroxynitrite, and downstream mechanisms including poly(ADP-ribose) polymerase (PARP) activation, is not limited to the diabetes-induced cardiovascular dysfunction, but also contributes to the development and progression of diabetic nephropathy, retinopathy and neuropathy. Accordingly, neutralization of peroxynitrite or pharmacological inhibition of PARP is a promising new approach in the therapy and prevention of diabetic complications. This review focuses on the role of nitrosative stress and downstream mechanisms including activation of PARP in diabetic complications and on novel emerging therapeutical strategies offered by neutralization of peroxynitrite and inhibition of PARP.

Fig. 1. Increased nitrotyrosine (NT) formation in diabetic tissues

Immunohistochemical staining for NT, an indicator of peroxynitrite formation, in control (left column), and 8 weeks old STZ-induced diabetic (right column) rat heart, kidney, retina and sciatic nerve tissue samples.

Fig. 2. Panel A. Reversal of diabetes-induced endothelial dysfunction by the porphyrinic peroxynitrite decomposition catalyst, FP15, in vascular rings from STZ-diabetic mice

Acetylcholine (Ach) induced endothelium-dependent relaxation is impaired in rings from diabetic mice, which is markedly improved by FP15 treatment. Each point of the curve represents the mean ± SEM of 5–7 pairs of experiments in vascular rings. *p< 0.05 in FP15 treated diabetic mice versus vehicle-treated diabetic mice. Panel B. Reversal of streptozotocin-evoked diabetes-induced diastolic cardiac dysfunction by the porphyrinic peroxynitrite decomposition catalyst, FP15, in mice. Effect of diabetes (9–10 weeks) and FP15 treatment in diabetic mice on left ventricular end diastolic pressure (LVEDP) and left ventricular -dP/dt (LV -dP/dt). Results are mean ± SEM of seven experiments in each group. *p< 0.05 diabetic animals versus control; #p< 0.05 in FP15-treated diabetic mice versus vehicle-treated diabetic mice. Reproduced with permission from 18.