Published Online
on August 11, 2003

A more recent version of this article appeared on August 26, 2003

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Submitted on November 11, 2002
Revised on April 22, 2003
Accepted on May 5, 2003

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

Asifa Haider PhD, Irene Lee MD, Jerzy Grabarek MD, PhD, Zbigniew Darzynkiewicz MD, PhD, and Nicholas R. Ferreri PhD^*

From the Department of Pharmacology, New York Medical College, Valhalla, NY.

^* To whom correspondence should be addressed. E-mail: nick_ferreri{at}nymc.edu.

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- 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 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.

Key words: prostaglandins • muscle, smooth • nitric oxide • thromboxane

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