Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion formation in apoE-deficient mice

Abstract

Nitric oxide (NO) derived from endothelial NO synthase (eNOS) is regarded as a protective factor against atherosclerosis. Therefore, augmentation of eNOS expression or NO production by pharmacological intervention is postulated to inhibit atherosclerosis. We crossed eNOS-overexpressing (eNOS-Tg) mice with atherogenic apoE-deficient (apoE-KO) mice to determine whether eNOS overexpression in the endothelium could inhibit the development of atherosclerosis. After 8 weeks on a high-cholesterol diet, the atherosclerotic lesion areas in the aortic sinus were unexpectedly increased by more than twofold in apoE-KO/eNOS-Tg mice compared with apoE-KO mice. Also, aortic tree lesion areas were approximately 50% larger in apoE-KO/eNOS-Tg mice after 12 weeks on a high-cholesterol diet. Expression of eNOS and NO production in aortas from apoE-KO/eNOS-Tg mice were significantly higher than those in apoE-KO mice. However, eNOS dysfunction, demonstrated by lower NO production relative to eNOS expression and enhanced superoxide production in the endothelium, was observed in apoE-KO/eNOS-Tg mice. Supplementation with tetrahydrobiopterin, an NOS cofactor, reduced the atherosclerotic lesion size in apoE-KO/eNOS-Tg mice to the level comparable to apoE-KO mice, possibly through the improvement of eNOS dysfunction. These data demonstrate that chronic overexpression of eNOS does not inhibit, but accelerates, atherosclerosis under hypercholesterolemia and that eNOS dysfunction appears to play important roles in the progression of atherosclerosis in apoE-KO/eNOS-Tg mice.

Stimulatory Roles of Nitric-oxide Synthase 3 and Guanylyl Cyclase in Platelet Activation

“…These factors play important physiological roles in vascular remodeling and wound repair and important pathological roles in vascular inflammation and in the development of atherosclerosis. In this respect it is interesting to note that despite the belief that NO is anti-atherosclerotic, recent studies showed that NOS3 promoted the development of atherosclerosis (40,41), as NOS3 knock-out mice are less prone to atherosclerosis, whereas overexpression of NOS3 in mice promotes atherosclerosis. Thus, the finding that NOS3 plays an important role in stimulating platelet secretion provides a potential mechanism for the role of NOS3 in promoting the development of atherosclerosis.…”

Endothelial arginase: A new target in atherosclerosis

“…In addition, increase in endogenous eNOS inhibitor asymmetric dimethylarginine (ADMA), deficiency in co-factor tetrahydrobiopterin (BH 4 ), and deficiency in the substrate L-arginine have been proposed to cause so-called "uncoupling of eNOS" in atherosclerosis, a situation in which eNOS produces free radical superoxide anion instead of NO [17,19]. This mechanism may further contribute to inactivation of bioactive NO in atherosclerosis mediated by oxidative stress mediated by other enzymes such as NADPHoxidase [19].…”

“…Most recently, a study with human coronary atherectomy specimens showed a higher eNOS gene expression in patients with acute coronary syndromes than those with stable angina [16]. It is of particular importance to note that Ozaki et al [17] recently showed acceleration of atherosclerotic lesion formation http://doc.rero.ch in ApoE -/-mice overexpressing bovine eNOS transgene. Controversial results were, however, reported by van Haperen et al [18] with the same experimental approach.…”

A proatherogenic role for cGMP-dependent protein kinase in vascular smooth muscle cells

“…Analysis of transgenic mice that lack or overexpress NO synthases indicated that NO exerts both protective (4,5) and atherogenic (6)(7)(8)(9) effects. The double role of NO might explain why NO-generating drugs (e.g., glyceryl trinitrate) have not been reported to limit the progression of atherosclerosis in humans.…”