Role of nitric oxide in diabetic complications.
Diabetic vascular disease is accompanied by decreased formation of the vasodilators, nitric oxide (NO), and prostacyclin and increased formation of vasoconstrictor eicosanoids, which exacerbate the progression of vascular disease. Similarities between the dysfunction introduced by short-term effects of elevated glucose and long-term effects of diabetes suggest that the alteration in endothelial factors in diabetes primarily results from exposure of endothelial cells to elevated glucose, although undoubtedly hyperlipidemia contributes as well. A key alteration in endothelial cell phenotype is increased formation of reactive oxygen species. This is in part due to uncoupling of endothelial NO synthase such that it generates superoxide anion in addition to NO. This is responsible for NO synthase to produce peroxynitrite, a damaging molecule. Peroxynitrite inactivates prostacyclin synthase leading to the accumulation of inflammatory and prothrombotic eicosanoids. This not only helps to explain the impairment of endothelial vasodilator mechanisms, but also increased progression of vascular disease. Many of these cellular abnormalities can be prevented by adequate scavenging of oxygen-derived free radicals or by blocking the actions of the eicosanoids at thromboxane (TP) receptors. Exposure to elevated glucose also gives rise to oxidants in smooth muscle, and recent studies indicate that oxidation of cysteine thiols under these conditions may prevent physiological NO signaling. As a result, the responsiveness to NO is impaired and accounts in part for abnormal endothelium-dependent vasodilation.
Cohen
Richard A
RA
Department of Medicine, Boston University School of Medicine, Boston, MA, USA. racohen@bu.edu
D048909:Diabetes Complications / Q000209:etiology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D014664:Vasodilation / Q000502:physiology
D009569:Nitric Oxide