Dual functionality of cyclooxygenase-2 as a regulator of tumor necrosis factor-mediated G(1) shortening and nitric oxide-mediated inhibition of vascular smooth muscle cell proliferation

Article

关键词: PROSTAGLANDIN I-2 SYNTHASE;    FACTOR-ALPHA;    THROMBOXANE A(2);    DEPENDENT INCREASES;    PROTEIN-KINASE;    MESSENGER-RNA;    RAT AORTA;    APOPTOSIS;    GROWTH;    EXPRESSION;   

DOI  :  10.1161/01.CIR.0000085211.97972.2C

来源: SCIE

【 摘 要 】

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 and Results - TNF-alpha stimulated proliferation of VSMCs by shortening the G(1) 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) I-2 synthesis, whereas thromboxane (TX) A(2) production and COX-2 protein expression were unaffected. Moreover, inhibition of NOS activity increased TNF-mediated proliferation by approximate to23%. Thus, NO preferentially stimulates PGI(2) 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 PGI(2) synthesis, had no effect on TXA(2) 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 PGI(2) derived from COX-2 might contribute to the antiproliferative effect of NO donors.

【 授权许可】

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