Free radicals in diabetic endothelial cell dysfunction.
Several studies have shown impairment of endothelium-dependent relaxations as well as increased release of vasoconstrictor prostanoids in arteries from diabetic animals and humans. This impairment is restored towards normal by prostaglandin (PG) H2/thromboxane A2 receptor blockade or superoxide dismutase, indicating that the PGH2 and/or superoxide anion (O2-.) generated contributes to the abnormality. Of particular note is that PGH2 impairs endothelium-dependent relaxations and causes contractions by a mechanism that involves generation of O2-. in the endothelium. The effects of elevated glucose are exacerbated by increased aldose reductase activity leading to depletion of NADPH and generation of reactive oxidants. Because NADPH is required for generation of nitric oxide from L-arginine, the depletion of NADPH leads to reduced nitric oxide formation. In a manner similar to that observed with elevated glucose, oxygen-derived free radicals or activation of protein kinase C also cause impairment of endothelium-dependent relaxations, smooth muscle contractions, and release constrictor prostanoids, indicating that a common mechanism for the impairment of endothelial cell function may be operative in diabetes. In this review the cumulative effects of oxidative stress on diabetic endothelial cell dysfunction, together with the complex interrelationship of cyclooxygenase catalysis, protein kinase C activity, and flux through the polyol pathway, are considered.
Tesfamariam
B
B
Department of Pharmacology, Bristol-Myers Squibb Research Institute, Princeton, NJ 08543.
D000818:Animals; D050260:Carbohydrate Metabolism; D003920:Diabetes Mellitus / Q000378:metabolism / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology*; D005609:Free Radicals; D006801:Humans; D011108:Polymers / Q000378:metabolism; D011453:Prostaglandins / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D014661:Vasoconstriction / Q000502:physiology
D005609:Free Radicals; D011108:Polymers; D011453:Prostaglandins; C024617:polyol; D011493:Protein Kinase C