Mechanisms of superoxide production in human blood vessels: relationship to endothelial dysfunction, clinical and genetic risk factors

K M Channon, T J Guzik
Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society 2002, 53 (4): 515-24
Common vascular disease states including diabetes, hypertension and atherosclerosis are associated with endothelial dysfunction, characterised by reduced bioactivity of nitric oxide (NO). Loss of the vasculoprotective effects of NO contributes to disease progression, but the mechanisms underlying endothelial dysfunction remain unclear. Increased superoxide production in animal models of vascular disease contributes to reduced NO bioavailability, endothelial dysfunction and oxidative stress. In human blood vessels, the NAD(P)H oxidase system is the principal source of superoxide, and is functionally related to clinical risk factors and systemic endothelial dysfunction. Furthermore, the C242T polymorphism in the NAD(P)H oxidase p22phox subunit is associated with significantly reduced superoxide production in patients carrying the 242T allele, suggesting a role for genetic variation in modulating vascular superoxide production. In vessels from patients with diabetes mellitus, endothelial dysfunction, NAD(P)H oxidase activity and protein subunits are significantly increased compared with matched non-diabetic vessels. Furthermore, the vascular endothelium in diabetic vessels is a net source of superoxide rather than NO production, due to dysfunction of endothelial NO synthase (eNOS). This deficit is dependent on the eNOS cofactor, tetrahydrobiopterin, and is in part mediated by protein kinase C signalling. These studies suggest an important role for both the NAD(P)H oxidases and endothelial NOS in the increased vascular superoxide production and endothelial dysfunction in human vascular disease states.

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