Reduction of Blood Pressure, Plasma Cholesterol, and Atherosclerosis by Elevated Endothelial Nitric Oxide

Abstract

In the vascular system, nitric oxide is generated by endothelial NO synthase (eNOS). NO has pleiotropic effects, most of which are believed to be atheroprotective. Therefore, it has been argued that patients suffering from cardiovascular disease could benefit from an increase in eNOS activity. However, increased NO production can cause oxidative damage, cell toxicity, and apoptosis and hence could be atherogenic rather than beneficial. To study the in vivo effects of increased eNOS activity, we created transgenic mice overexpressing human eNOS. Aortic blood pressure was ϳ20 mm Hg lower in the transgenic mice compared with control mice because of lower systemic vascular resistance. The effects of eNOS overexpression on diet-induced atherosclerosis were studied in apolipoprotein E-deficient mice. Elevation of eNOS activity decreased blood pressure (ϳ20 mm Hg) and plasma levels of cholesterol (ϳ17%), resulting in a reduction in atherosclerotic lesions by 40%. We conclude that an increase in eNOS activity is beneficial and provides protection against atherosclerosis.

Endothelial Nitric Oxide Synthase Overexpression Restores the Efficiency of Bone Marrow Mononuclear Cell-Based Therapy

“…It is likely that the potent anti-inflammatory effect of eNOS overexpression is the main responsible factor in the antiatherogenic effect of eNOS transgenic ApoE KO BMMNC treatment, as described previously. 11 Definitely, further studies will be necessary to investigate in more detail not only our interesting observation of the combined proangiogenic and antiatherogenic potential of eNOS cell-based therapy but also the complete concept of BMMNCs treatment-induced atherogenesis. Nevertheless, these results imply that eNOS up-regulation is a promising target for local or stem cell-based therapeutic neovascularization in patients with ischemic (cardio)vascular disease.…”

“…C57BL/6 and apolipoprotein E-deficient (ApoE KO) transgenic mice overexpressing the human eNOS gene under regulation of the human eNOS promoter were obtained, as previously described. 11 Mice were backcrossed to C57Bl6 for at least 10 generations (Ͼ96% C57Bl6). To induce diabetes, 8-week-old mice were injected intraperitoneally with 40 mg/kg of streptozotocin (Sigma-Aldrich Corp, St. Louis, MO) in 0.05 mol/L sodium citrate, pH 4.5, daily for 5 days.…”

“…9,10 Thus, impaired bioavailability of NO may significantly contribute to the impaired neovascularization response to ischemia in atherosclerosis or diabetes. Therefore, using homebred transgenic mice overexpressing human eNOS, 11 the purposes of the present study were to evaluate whether eNOS gene therapy would be able to improve the postischemic neovascularization response in diabetes and atherosclerosis and to restore the impaired proangiogenic potential of BMMNCs without causing simultaneous detrimental proatherogenic effects, overcoming the Janus phenomenon.…”

Atherosclerotic Lesion Size and Vulnerability Are Determined by Patterns of Fluid Shear Stress

“…12-14 Upregulation of eNOS expression could be part of the antiatherogenic properties of increased shear stress. 15 Indeed, we previously found that eNOS is elevated in cast-induced increased shear stress vessel segments. 8 At later times, only small lesions were found in some of the treated apoEϪ/Ϫ mice (lesion size was not different from that in the control region).…”

Endothelial arginase: A new target in atherosclerosis

“…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. The discrepancies in the results of the two studies are not clear.…”