摘要：

Superoxide plays important roles in vascular function and structure. In atherosclerotic vessels, superoxide production is increased and it is revealed that NAD (P) H oxidase plays a central role in its production in vessels. We showed that superoxide production is increased in association with augmented expression of p22Phox, a subcomponent of NAD (P) H oxidase, in atheromatous plaques of coronary arteries obtained from autopsy patients and also in samples obtained by directional coronary atherectomy (DCA). Interestingly, superoxide production is higher in samples from patients from unstable angina compared with those from stable angina. We also revealed the importance of angiotensin II as the activator of superoxide production in atherosclerotic vessels. In apo E knockout mice (apo E-KO), chronic treatment with telmisartan reduced atherosclerotic lesion size independently of its action on blood pressure. This effect was associated with reduced superoxide production.Recently endothelial NO synthase (eNOS) has attracted attention as a superoxide producing enzyme. It is revealed that eNOS becomes dysfunctional and produces superoxide rather than NO under conditions in which vascular tissue levels of BH4, a co-factor for eNOS, are deficient or lacking. Experimental studies in vitro have revealed that NO from eNOS functions as an anti-atherogenic molecule. In eNOS-knockout mice, eNOS deficiency augments atherosclerotic lesion formation, although the effects may be partly due to associated hypertension. We crossed eNOS-transgenic mice (eNOS-Tg) overexpressing eNOS in the endothelium with apo E-KO, and demonstrated that under hypercholesterolemia eNOS overexpression accelerated atherosclerotic lesion formation in association with increased superoxide production from vessels compared with apo E-KO mice. In these mice, vascular tissue levels of BH4 were reduced and BH2, an oxidized form, levels were increased. Chronic administration of exogenous BH4 or overexpression of GTPCH-1, a rate limiting enzyme for BH4 synthesis, restored the lesion to the levels comparable to apoE-KO mice. Therefore, under hypercholesterolemia the overexpressed eNOS became dysfunctional and produced superoxide, which accelerated atherogenesis. eNOS may have 2 faces in the pathophysiology of atherosclerosis depending on tissue BH4 levels.

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