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(Circulation. 2003;108:1015.)
© 2003 American Heart Association, Inc.

Basic Science Reports

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; Nicholas R. Ferreri, PhD

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

Correspondence to Dr Nicholas R. Ferreri, New York Medical College, Department of Pharmacology, Valhalla, NY 10595. E-mail nick_ferreri{at}nymc.edu

Received November 11, 2002; revision received April 22, 2003; accepted May 5, 2003.

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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