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

Pál Pacher, Irina G. Obrosova, Jon G. Mabley, Csaba Szabo

Research output: Contribution to journalArticle

262 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)267-275
Number of pages9
JournalCurrent Medicinal Chemistry
Volume12
Issue number3
StatePublished - 2005
Externally publishedYes

Fingerprint

Peroxynitrous Acid
Poly(ADP-ribose) Polymerases
Diabetes Complications
Medical problems
Superoxides
Chemical activation
Diabetic Neuropathies
Cytotoxins
Vascular Endothelium
Diabetic Nephropathies
Biomolecules
Diabetic Retinopathy
Vascular Smooth Muscle
Hyperglycemia
Protein Kinase C
Macros
Muscle
Myocardium
Diabetes Mellitus
Nitric Oxide

Keywords

  • Cardiomyopathy
  • Diabetes
  • Nephropathy
  • Neuropathy
  • Nitric oxide
  • Nitrotyrosine
  • Peroxynitrite
  • Retinopathy
  • Superoxide
  • Vascular

ASJC Scopus subject areas

  • Organic Chemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Pharmacology

Cite this

Role of nitrosative stress and peroxynitrite in the pathogenesis of diabetic complications. Emerging new therapeutical strategies. / Pacher, Pál; Obrosova, Irina G.; Mabley, Jon G.; Szabo, Csaba.

In: Current Medicinal Chemistry, Vol. 12, No. 3, 2005, p. 267-275.

Research output: Contribution to journalArticle

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