title: 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.
authors.affiliation: Laboratory of Physiologic Studies, National Institutes of Health, NIAAA, Bethesda, MD 20892-9413, USA. ppacher@lycos.com
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
authors.forename: Irina G
authors.initials: IG
authors.lastname: Obrosova
authors.forename: Jon G
authors.initials: JG
authors.lastname: Mabley
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabó
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology / Q000378:metabolism; D048909:Diabetes Complications / Q000209:etiology / Q000378:metabolism*; D003925:Diabetic Angiopathies / Q000209:etiology; D003928:Diabetic Nephropathies / Q000209:etiology; D003929:Diabetic Neuropathies / Q000209:etiology; D003930:Diabetic Retinopathy / Q000209:etiology; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D013481:Superoxides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D011065:Poly(ADP-ribose) Polymerases
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