Role of nitrosative stress and poly(ADP-ribose) polymerase activation in diabetic vascular dysfunction.
Complications of diabetes rather than the primary disease itself pose the most challenging aspects of diabetic patient management. Diabetic vascular dysfunction represents a problem of great clinical importance underlying the development of many of the complications including retinopathy, neuropathy and the increased risk of stroke, hypertension and myocardial infarction. Hyperglycaemia stimulates many cellular pathways, which result in oxidative stress, including increased production of advanced glycosylated end products, protein kinase C activation, and polyol pathway flux. Endothelial cells produce nitric oxide constitutively to regulate normal vascular tone; the combination of this nitric oxide with the hyperglycaemia-induced superoxide formation results in the production of reactive nitrogen species such as peroxynitrite. This nitrosative stress results in many damaging cellular effects, but it is these effects on DNA, which are the most damaging to the cell function; nitrosative stress induces DNA single stand breaks and leads to over-activation of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP). PARP activation contributes to endothelial cell dysfunction and appears to be the central mediator in all the mechanisms by which hyperglycaemia-induces diabetic vascular dysfunction. This review focuses on the mechanism by which hyperglycaemia induces nitrosative stress and the role PARP activation plays in diabetic vascular dysfunction.
Mabley
Jon G
JG
School of Pharmacy and Biomolecular Sciences, University of Brighton, Cockcroft Building, UK. J.G.Mabley@brighton.ac.uk
Soriano
Francisco Garcia
FG
D000818:Animals; D048909:Diabetes Complications / Q000378:metabolism*; D003925:Diabetic Angiopathies / Q000209:etiology; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D018384:Oxidative Stress; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D011065:Poly(ADP-ribose) Polymerases