Published online before print March 4, 2004, doi: 10.1161/01.ATV.0000125114.88079.96
© 2004 American Heart Association, Inc.
Brief Reviews |
Dysfunction of Endothelial Nitric Oxide Synthase and Atherosclerosis
From the Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kusunoki-cho Chuo-ku Kobe, 0017, Japan.
Correspondence to Dr Mitsuhiro Yokoyama, Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho Chuo-ku Kobe, 650-0017, Japan. E-mail yokoyama{at}med.kobe-u.ac.jp
Atherosclerosis is associated with an impairment of endothelium-dependent relaxations, which represents the reduced bioavailability of nitric oxide (NO) produced from endothelial NO synthase (eNOS). Among various mechanisms implicated in the impaired EDR in atherosclerosis, superoxide generated from dysfunctional eNOS has attracted attention. Under conditions in which vascular tissue levels of tetrahydrobiopterin (BH4), a cofactor for NOS, are deficient or lacking, eNOS becomes dysfunctional and produces superoxide rather than NO. Experimental studies in vitro have revealed that NO from eNOS constitutes an anti-atherogenic molecule. A deficiency of eNOS was demonstrated to accelerate atherosclerotic lesion formation in eNOS knockout mice. In contrast, eNOS overexpression with hypercholesterolemia may promote atherogenesis via increased superoxide generation from dysfunctional eNOS. Thus, eNOS may have 2 faces in the pathophysiology of atherosclerosis depending on tissue BH4 metabolisms. An improved understanding of tissue BH4 metabolisms in atherosclerotic vessels is needed, which would help in developing new strategies for the inhibition and treatment of atherosclerosis.
In hyperlipidemia and atherosclerosis, eNOS may become dysfunctional because of a lack or deficiency of tissue levels of tetrahydrobiopterin and produces superoxide rather than NO, which leads to the impaired endothelial function. The role of dysfunctional eNOS in atherogenesis is an important issue to be clarified.
Key Words: endothelial nitric oxide synthase • atherosclerosis • tetrahydrobiopterin • superoxide • nitric oxide
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