The mutation of the potential heme-binding site of the p22 phox gene may reduce susceptibility to CAD. Our observations suggest that the C242T polymorphism of the p22 phox gene is a novel genetic marker that has a protective effect on coronary risk.

Chronic eNOS overexpression in the endothelium of mice resulted in resistance to LPS-induced hypotension, lung injury, and death. These effects are associated with the reduced vascular reactivity to NO and the reduced anti-inflammatory effects of NO.

The 5A/6A polymorphism in the promoter of the stromelysin gene is a novel pathogenetic risk factor for AMI.

Abstract-NO, constitutively produced by endothelial NO synthase (eNOS), plays a key regulatory role in vascular wall homeostasis. We generated transgenic (Tg) mice overexpressing eNOS in the endothelium and reported the presence of reduced NO-elicited relaxation. The purpose of this study was to clarify mechanisms of the reduced response to NO-mediated vasodilators in eNOS-Tg mice. Thoracic aortas of Tg and control mice were surgically isolated for vasomotor studies. Relaxations to acetylcholine and sodium nitroprusside were significantly reduced in Tg vessels compared with control vessels. Relaxations to atrial natriuretic peptide and 8-bromo-cGMP were also significantly reduced in Tg vessels. Reduced relaxations to these agents were restored by chronic N G -nitro-L-arginine methyl ester treatment. Basal cGMP levels of aortas were higher in Tg mice than in control mice, whereas soluble guanylate cyclase (sGC) activity in Tg vessels was Ϸ50% of the activity in control vessels. Moreover, cGMP-dependent protein kinase (PKG) protein levels and PKG enzyme activity were decreased in Tg vessels. These observations indicate that chronic overexpression of eNOS in the endothelium resulted in resistance to the NO/cGMP-mediated vasodilators and that at least 2 distinct mechanisms might be involved: one is reduced sGC activity, and the other is a decrease in PKG protein levels. We reported for the first time that increased NO release from the endothelium reduces sGC and PKG activity in mice. These data may provide a new insight into the mechanisms of nitrate tolerance and cross tolerance to nitrovasodilators. Key Words: nitric oxide synthase Ⅲ mice, transgenic Ⅲ guanylyl cyclase Ⅲ protein kinases N itric oxide plays critical roles in vascular biology, including its action on vascular tone and regulation of vascular structure. 1 In physiological conditions, NO is mainly produced by endothelial NO synthase (eNOS) in vessels. eNOS produces small amounts of NO continuously by physiological stimuli, such as shear stress and endogenous vasoactive substances. 2 Released NO diffuses to overlying vascular smooth muscle and binds to the ferrous heme moiety of soluble guanylate cyclase (sGC), thereby activating the enzyme. Activated sGC converts guanosine triphosphate to the intracellular second messenger cGMP, which relaxes vascular smooth muscle cells. 3 Most of the effects of cGMP are mediated by stimulation of the cGMP-dependent protein kinase (PKG). 4 Recently, we generated transgenic (Tg) mice overexpressing the bovine eNOS gene in endothelial cells. The Tg mice exhibited increased basal NO production and basal cGMP levels in the vascular wall. Furthermore, in previous reports, we found that the overproduction of NO caused reduced endothelium-dependent and NO-mediated relaxations without changes in cAMP-mediated relaxation. 5,6 Those were the first reports indicating that increased intrinsic NO induced resistance to NO-mediated vasodilators. This alteration in vascular reactivity resembles "nitrate tolerance." Organic nitrates i...

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