Kietadisorn R, Juni RP, Moens AL. Tackling endothelial dysfunction by modulating NOS uncoupling: new insights into its pathogenesis and therapeutic possibilities. Am J Physiol Endocrinol Metab 302: E481-E495, 2012. First published December 13, 2011 doi:10.1152/ajpendo.00540.2011.-Endothelial nitric oxide synthase (eNOS) serves as a critical enzyme in maintaining vascular pressure by producing nitric oxide (NO); hence, it has a crucial role in the regulation of endothelial function. The

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... bility of eNOS-derived NO is crucial for this function and might be affected at multiple levels. Uncoupling of eNOS, with subsequently less NO and more superoxide generation, is one of the major underlying causes of endothelial dysfunction found in atherosclerosis, diabetes, hypertension, cigarette smoking, hyperhomocysteinemia, and ischemia/reperfusion injury. Therefore, modulating eNOS uncoupling by stabilizing eNOS activity, enhancing its substrate, cofactors, and transcription, and reversing uncoupled eNOS are attractive therapeutic approaches to improve endothelial function. This review provides an extensive overview of the important role of eNOS uncoupling in the pathogenesis of endothelial dysfunction and the potential therapeutic interventions to modulate eNOS for tackling endothelial dysfunction. endothelial dysfunction; nitric oxide synthase; nitric oxide synthase uncoupling; superoxide