Dual functionality of cyclooxygenase-2 as a regulator of tumor necrosis factor-mediated G1 shortening and nitric oxide-mediated inhibition of vascular smooth muscle cell proliferation.
Circulation
; 108(8): 1015-21, 2003 Aug 26.
Article
em En
| MEDLINE
| ID: mdl-12912810
ABSTRACT
BACKGROUND:
Cyclooxygenase (COX)-2 contributes to vascular smooth muscle cell (VSMC) proliferation induced by tumor necrosis factor (TNF) and angiotensin II. The present study demonstrates, however, that depending on prevailing conditions, COX-2-derived prostanoids may also inhibit VSMC proliferation. METHODS ANDRESULTS:
TNF-alpha stimulated proliferation of VSMCs by shortening the G1 phase of the cell cycle. This effect was abolished by NS-398, a selective COX-2 inhibitor. Addition of TNF did not affect the protein-to-DNA ratio, measured by flow cytometry, suggesting that TNF does not induce VSMC hypertrophy. Inhibition of nitric oxide synthase (NOS) activity attenuated TNF-mediated increases in prostaglandin (PG) I2 synthesis, whereas thromboxane (TX) A2 production and COX-2 protein expression were unaffected. Moreover, inhibition of NOS activity increased TNF-mediated proliferation by approximately 23%. Thus, NO preferentially stimulates PGI2 production, suggesting that production of NO by VSMCs challenged with TNF limits the ability of the cytokine to increase proliferation. NO donors increased COX-2 protein expression and PGI2 synthesis, had no effect on TXA2 production, and decreased cell numbers by 50%, indicating that expression of COX-2 per se might not be sufficient to support proliferation. The effects of NO donors were prevented when COX-2 activity was inhibited with NS-398.CONCLUSIONS:
The COX-2-dependent proliferative response of VSMCs to TNF was modulated in an NO-dependent manner, and PGI2 derived from COX-2 might contribute to the antiproliferative effect of NO donors.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fase G1
/
Fator de Necrose Tumoral alfa
/
Prostaglandina-Endoperóxido Sintases
/
Isoenzimas
/
Músculo Liso Vascular
/
Óxido Nítrico
Limite:
Animals
Idioma:
En
Ano de publicação:
2003
Tipo de documento:
Article