Nitric Oxide–Generating Compounds Inhibit Total Protein and Collagen Synthesis in Cultured Vascular Smooth Muscle Cells

Kolpakov, Valeri; Gordon, David; Kulik, Thomas J.

doi:10.1161/01.res.76.2.305

Cited by 249 publications

(137 citation statements)

References 21 publications

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“…Previous experiments have demonstrated that NO donors added directly to the VSMC growth medium decreased collagen I concentrations, but not collagen III concentrations. 21 Kolpakov et al 22 have also previously found that NO inhibits total protein and collagen synthesis in noncoronary VSMCs.…”

Section: Discussionmentioning

confidence: 89%

“…Prior research has demonstrated that NO donors alter collagen metabolism when added directly to VSMCs 21,22 ; however, less is known with regard to the role of endogenously derived NO in vascular wall extracellular matrix metabolism. Since previous work has established that NO is produced by an endothelial constitutive enzyme, the experimental design employed a NOS antagonist to block endogenous synthesis of NO.…”

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confidence: 99%

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Vascular Endothelial Cell Regulation of Extracellular Matrix Collagen

Myers

Tanner

1998

ATVB

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Abstract-Endothelium-derived products have been implicated in the regulation of vascular wall structure through their effects on extracellular matrix metabolism. The purpose of this study was to further understand the paracrine mechanisms underlying endothelial cell regulation of extracellular matrix metabolism by testing the hypothesis that endothelium-derived nitric oxide decreases the concentration of soluble collagens derived from vascular smooth muscle cells (VSMCs). Porcine coronary endothelium and VSMCs were grown under a coculture configuration to assess the paracrine effects of nitric oxide produced by the endothelium on VSMC collagen types I and III. Endogenous endothelial cell nitric oxide production was blocked with N -nitro-L-arginine methyl ester. Collagen type I and type III were quantitatively measured using an enzyme-linked immunosorbent assay method. The endothelium elicited a timedependent increase in the concentration of soluble VSMC-derived collagen type I; in contrast, collagen type III was decreased. After inhibition of nitric oxide production, there was a marked increase in both collagen types I and III concentration. These results demonstrated that endothelium-derived nitric oxide differentially alters collagen subtypes produced by VSMCs. The data support the hypothesis that nitric oxide functions via a paracrine mechanism to decrease VSMC collagen types I and III concentration, a finding consistent with an integral role for the endothelium in modulating extracellular matrix metabolism. (Arterioscler Thromb Vasc Biol. 1998;18:717-722.) Key Words: extracellular matrix Ⅲ nitric oxide Ⅲ collagen Ⅲ endothelium N itric oxide is an endothelium-derived compound that exerts multiple effects on the vasculature through its paracrine actions on the vessel wall, as well as on formed blood elements. The vasomotor actions of NO are well characterized (for review, see Reference 1). Nitric oxide also is a potent inhibitor of platelet aggregation, 2,3 an antimitogen, 4-7 an inhibitor of cell migration, 8 and an immunomodulator.9 -11 Alterations and/or abnormalities in NO metabolism have been implicated in a variety of diseases, especially atherosclerosis 12-15 and, more recently, restenosis. 16,17 The multiple actions of NO and its role in vascular wall disease are consistent with an important role in the metabolism of the extracellular matrix.The vascular wall extracellular matrix comprises the bulk of the interstitium of the media and is composed of a complex mixture of extracellular matrix proteins, including collagens. 18 The fibrillar collagens are the most abundant collagens, with subtypes I, III, and IV being most common. 18,19 Atherogenesis and restenosis are two disease processes relevant to coronary artery vascular biology that are directly related to extracellular matrix collagen synthesis and degradation, primarily because the hallmark of the disease is mechanical obstruction of coronary blood flow secondary to medial and intimal hyperplasia. The importance of a functionally intact endotheliu...

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Section: Discussionmentioning

confidence: 89%

mentioning

confidence: 99%

Vascular Endothelial Cell Regulation of Extracellular Matrix Collagen

Myers

Tanner

1998

ATVB

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“…There are reports that NO inhibits protein synthesis (40)(41)(42) at the level of translation initiation. Translation initiation depends mainly on the activity of eukaryotic initiation factors (eIFs).…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide-induced cytostasis and cell cycle arrest of a human breast cancer cell line (MDA-MB-231): Potential role of cyclin D1

Pervin

Singh

Chaudhuri

2001

Proc. Natl. Acad. Sci. U.S.A.

160

115

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DETA-NONOate, a nitric oxide (NO) donor, induced cytostasis in the human breast cancer cells MDA-MB-231, and the cells were arrested in the G 1 phase of the cell cycle. This cytostatic effect of the NO donor was associated with the down-regulation of cyclin D1 and hypophosphorylation of the retinoblastoma protein. No changes in the levels of cyclin E or the catalytic partners of these cyclins, CDK2, CDK4, or CDK6, were observed. This NO-induced cytostasis and decrease in cyclin D1 was reversible for up to 48 h of DETA-NONOate (1 mM) treatment. DETA-NONOate (1 mM) produced a steady-state concentration of 0.5 M of NO over a 24-h period. Synchronized population of the cells exposed to DETANONOate remained arrested at the G 1 phase of the cell cycle whereas untreated control cells progressed through the cell cycle after serum stimulation. The cells arrested at the G 1 phase after exposure to the NO donor had low cyclin D1 levels compared with the control cells. The levels of cyclin E and CDK4, however, were similar to the control cells. The decline in cyclin D1 protein preceded the decrease of its mRNA. This decline of cyclin D1 was due to a decrease in its synthesis induced by the NO donor and not due to an increase in its degradation. We conclude that down-regulation of cyclin D1 protein by DETA-NONOate played an important role in the cytostasis and arrest of these tumor cells in the G 1 phase of the cell cycle.A ctivated macrophages produce large amounts of nitric oxide (NO), which induces cytostasis and cytotoxicity to tumor cells both in vitro and in vivo (1-8). Macrophages also play a significant role in host resistance to tumors (7-9). Tumor cells cocultured with activated macrophages rapidly develop cytostasis, which precedes the cytotoxic effects (5, 10).It has been reported that NO-induced early cytostasis begins with a rapid and reversible inhibition of ribonucleotide reductase (RR) (10). However, the possibility of targets other than RR being involved in the NO-induced long-lasting cytostasis was suggested by other investigators (10). Hydroxyurea, a specific inhibitor of RR (10), decreased thymidine incorporation in cultured cells and, after its removal, the thymidine incorporation rapidly returned to control values. The rate of recovery was much faster after withdrawal of hydroxyurea when compared with the rate of recovery observed in cells that initially were exposed either to activated macrophages or to a NO donor and then kept in a NO-free environment. On this basis, it was suggested that targets other than RR may be responsible for producing long-lasting cytostasis in target cells exposed to NO (5,10,11). This long-lasting cytostasis, therefore, would be associated with metabolic alterations in target cells, producing long-lasting growth inhibition and requiring a longer time for these cells to resume their normal rate of proliferation.Because the precise mechanism(s) by which NO induces this long-lasting cytostasis is not completely known, the present work was undertaken to assess this mechanism(s)...

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“…23 Furthermore, expression of PDGF receptors is a consistent feature of the process of HSC activation in vitro and in vivo. 21,23 NO donors have been shown to reduce collagen type I deposition in vascular smooth muscle cells and in human HSCs, 24,25 and NO release induced by proinflammatory cytokines has been proven responsible for the inhibition of ␣-smooth muscle actin expression, a marker of HSC activation. 26 In addition, a possible direct antifibrogenic effect of NO donors is suggested by in vitro studies showing antiproliferative and antichemotactic actions of these compounds in vascular smooth muscle cells and glomerular mesangial cells.…”

Section: E Xperimental and Clinical Studies Have Indicated Thatmentioning

confidence: 99%

Nitrovasodilators inhibit platelet-derived growth factor-induced proliferation and migration of activated human hepatic stellate cells

Failli¹,

et al. 2000

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Background & Aims:Nitrovasodilators have been proposed for the treatment of portal hypertension alone or in combination with ␤-blockers. In addition to their vasodilatory properties, nitric oxide (NO) donors may exert direct antifibrogenic properties. We evaluated the effect of nitroglycerin (NTG) and S-nitroso-N-acetyl penicillamine (SNAP) on the mitogenic and chemotactic properties of platelet-derived growth factor (PDGF)-BB and the modulation of the relative intracellular signaling pathways in fully activated human hepatic stellate cells (HSCs), a cell type that plays an active role in liver fibrogenesis and portal hypertension. Methods & Results: Both NTG and SNAP induced a dosedependent decrease in PDGF-induced DNA synthesis and cell migration, which was associated with a decrease in PDGF-induced intracellular Ca 2؉ increase and extracellular signal-regulated kinase (ERK) activity. These effects were not related to activation of the classic soluble guanylate cyclase (sGC)/guanosine 3 ,5 -cyclic monophosphate pathway; accordingly, Western blot analysis of HSC lysates revealed the absence of the ␣ 1 ␤ 1 ubiquitous subunits of sGC, whereas they were detectable in quiescent HSCs, freshly isolated from normal human liver. Conversely, both NTG and SNAP induced a more than 10 -20-fold increase in prostaglandin E 2 in cell supernatants within 1 minute, associated with an increase in intracellular adenosine 3 ,5 -cyclic monophosphate levels. Accordingly, the inhibitory effects of NO donors on PDGF action and signaling were eliminated after preincubation with ibuprofen. Conclusions: These results suggest that NO donors may exert a direct antifibrogenic action by inhibiting proliferation, motility, and contractility of HSCs in addition to a reduction of fibrillar extracellular matrix accumulation.

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Nitric Oxide–Generating Compounds Inhibit Total Protein and Collagen Synthesis in Cultured Vascular Smooth Muscle Cells

Cited by 249 publications

References 21 publications

Vascular Endothelial Cell Regulation of Extracellular Matrix Collagen

Vascular Endothelial Cell Regulation of Extracellular Matrix Collagen

Nitric oxide-induced cytostasis and cell cycle arrest of a human breast cancer cell line (MDA-MB-231): Potential role of cyclin D1

Nitrovasodilators inhibit platelet-derived growth factor-induced proliferation and migration of activated human hepatic stellate cells

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