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Effect of nitric oxide and peroxynitrite on type I collagen synthesis in normal and scleroderma dermal fibroblasts

Dooley, A; Gao, BR; Xu, SW; Abraham, DJ; Black, CM; Jacobs, M; Bruckdorfer, KR; (2007) Effect of nitric oxide and peroxynitrite on type I collagen synthesis in normal and scleroderma dermal fibroblasts. FREE RADICAL BIO MED , 43 (2) 253 - 264. 10.1016/j.freeradbiomed.2007.04.017.

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Abstract

Nitric oxide ((NO)-N-.) is an important physiological signaling molecule and potent vasodilator. Recently, we have shown abnormal (NO)-N-. metabolism in the plasma of patients with systemic sclerosis (SSc), a disease that features excessive collagen overproduction as well as vascular dysfunction. The current study investigates the effects of (NO)-N-. and peroxynitrite (ONOO-) on secretion of type I collagen by SSc dermal fibroblasts, compared with those from normal dermal fibroblasts (CON) and a dermal fibroblast cell line (AG). Dermal fibroblasts were incubated with (NO)-N-. donors (SNP, DETA-NONOate) with or without the antioxidant ascorbic acid, or ONOO- for 24-72 h. In CON and AG fibroblasts, type I collagen was dose dependently decreased by SNP or DETA-NONOate. However, (NO)-N-. had no effect in SSc fibroblasts. Furthermore, the inhibition of collagen synthesis by (NO)-N-. was reversed by ascorbic acid and was not affected by 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1 -one, ail inhibitor of soluble guanyl cyclase, or 8-bromoguanosine cyclic 3,5'-monophosphate, a cGMP agonist. SNP also showed a significant upregulation of matrix metalloproteinase-1 (MMP-1) protein and activity levels, ail essential collagenase involved in collagen degradation, in the AG fibroblasts. Additionally, (NO)-N-.-treated fibroblasts had lower prolyl hydroxylase activity, an enzyme important in the post-translational processing of collagen, while there was no effect on total protein levels. There were no significant effects on type I collagen levels when dermal fibroblasts were treated with ONOO-. Taken together, (NO)-N-. inhibits collagen secretion in normal dermal fibroblasts but regulation is lost in SSc fibroblasts, while ONOO- itself is ineffective. .NO inhibition of collagen was by cGMP-independent regulatory mechanisms and in part may be due to upregulation of MMP-1 and/or inhibition of prolyl hydroxylase. These differences may contribute to the observed pathology of SSc. (C) 2007 Elsevier Inc. All rights reserved.

Type: Article
Title: Effect of nitric oxide and peroxynitrite on type I collagen synthesis in normal and scleroderma dermal fibroblasts
DOI: 10.1016/j.freeradbiomed.2007.04.017
Keywords: nitric oxide, fibroblast, type I collagen, systemic sclerosis, ascorbic acid, free radicals, peroxynitrite, GROWTH-FACTOR-BETA, LOW-DENSITY LIPOPROTEINS, SMOOTH-MUSCLE-CELLS, RAT MESANGIAL CELLS, SYSTEMIC-SCLEROSIS, PROLYL 4-HYDROXYLASE, ASCORBIC-ACID, RAYNAUDS-PHENOMENON, ENDOTHELIAL-CELLS, OXIDATIVE STRESS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: http://discovery.ucl.ac.uk/id/eprint/100177
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