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      Does Nitric Oxide Regulate Smooth Muscle Cell Proliferation?

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          Smooth muscle proliferation is involved in the pathogenesis of atherosclerosis, restenosis after angioplasty and vein graft failure due to neointimal hyperplasia. Nitric oxide (NO) inhibits smooth muscle cell growth in vitro and experimental neointimal hyperplasia in vivo, suggesting a role for NO as a regulator of smooth muscle cell proliferation. NO is also involved in the control of numerous other vascular functions including platelet and inflammatory cell adhesion, vascular reactivity and endothelial permeability. This review critically examines the experimental and clinical evidence that supports a role for NO as a modulator of smooth muscle cell proliferation, with an emphasis on the multiple mechanisms by which NO acts on vascular lesions.

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          Most cited references 11

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          Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine

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            p53 expression in nitric oxide-induced apoptosis.

            Nitric oxide (NO) is a diffusible messenger involved in several patho-physiological processes including immune-mediated cytotoxicity and neural cell killing. NO or the products of its redox chemistry can cause DNA damage and activate subsequent lethal reactions including energy depletion and cell necrosis. However, regardless of whether it is endogenously produced in response to cytokines, or generated by chemical breakdown of donor molecules, NO can also induce apoptosis in different systems. Here, we report that NO generation in response to a cytokine induced NO-synthase or by NO donors stimulates the expression of the tumor suppressor gene, p53, in RAW 264.7 macrophages or pancreatic RINm5F cells prior to apoptosis. NO-synthase inhibitors such as NG-monomethyl-L-arginine prevent the inducible NO generation as well as p53 expression and apoptosis. Since p53 expression is linked to apoptosis in some cells exposed to DNA damaging agents, we suggest that NO-induced apoptosis in these cell systems is the consequence of DNA damage and subsequent expression of this tumor suppressor gene.
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              Induction of the cyclin-dependent kinase inhibitor p21(Sdi1/Cip1/Waf1) by nitric oxide-generating vasodilator in vascular smooth muscle cells.

              Nitric oxide-generating vasodilators inhibit vascular smooth muscle cell proliferation. To elucidate the mechanism underlying this process, we investigated the effect of S-nitroso-N-acetylpenicillamine (SNAP), a nitric oxide-releasing agent, on the smooth muscle cell cycle. When G0 cells were stimulated with fetal bovine serum and basic fibroblast growth factor, DNA synthesis assessed by [3H]thymidine incorporation started about 15 h later. SNAP dose-dependently inhibited this incorporation, and this effect was maximal at 100 microM. This inhibition was attenuated when SNAP was added after 9-12 h. SNAP inhibited the activity of cyclin-dependent kinase 2 (Cdk2) and phosphorylation of the retinoblastoma protein, both of which usually increased from about 9 h, whereas it did not inhibit the activities of cyclin D-associated kinase(s), Cdk4, and Cdk6, which normally increased from 0-3 h. Although SNAP reduced the mRNA levels of cyclins E and A, it neither reduced their protein levels nor impaired their association with Cdk2. SNAP did not reduce the mRNA levels of cyclins G, C, and D1, Cdk2, Cdk4, and Cdk5, which were normally elevated from 0-3 h. The mRNA and protein levels of the Cdk inhibitor p21 were high in the early G1 phase, peaking at 3 h and then rapidly decreasing after 6 h. In the presence of SNAP, however, p21 expression was enhanced, and moreover, the later decrease disappeared. SNAP also increased the amount of Cdk2-associated p21. These results suggested that nitric oxide inhibits the G1/S transition by inhibiting Cdk2-mediated phosphorylation of the retinoblastoma protein and that p21 induction is involved in the Cdk2 inhibition.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                June 1998
                09 June 1998
                : 35
                : 3
                : 135-142
                a Department of Surgery, University of California (Los Angeles) Medical Center, Los Angeles, Calif., and b Department of Physiology, University of Michigan Medical School, Ann Arbor, Mich., USA
                25576 J Vasc Res 1998;35:135–142
                © 1998 S. Karger AG, Basel

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                Page count
                Figures: 2, References: 69, Pages: 8


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