Cyclooxygenase-2 is required for tumor necrosis factor-α- and angiotensin II-mediated proliferation of vascular smooth muscle cells

Abstract

Tumor necrosis factor-α (TNF-α) and angiotensin II (Ang II) induced a transient increase in vascular smooth muscle cell (VSMC) cyclooxygenase-2 (COX-2) mRNA accumulation, without affecting COX-1 mRNA levels. The kinetics of COX-2 mRNA accumulation were similar in VSMCs challenged with either TNF- α or Ang II; mRNA accumulation peaked at 2 hours and decreased to control levels by ≃6 hours. Accumulation of COX-2 mRNA was associated with a time- dependent increase of COX-2 protein expression that displayed similar kinetics in response to either TNF-α or Ang II. Both the increase in COX-2 mRNA accumulation and protein expression in response to either TNF-α or Ang II were inhibited by the mitogen-activated protein/extracellular signal- regulated kinase (MEK) inhibitor PD098059. In addition, the AT1-selective receptor antagonist losartan attenuated the Ang II-mediated increase in COX-2 mRNA accumulation; the AT2-selective antagonist PD123319 had no effect. Prostacyclin I2 synthesis was tightly coupled to expression of COX-2, whereas prostaglandin E2 and thromboxane A2 (TXA2) synthesis may be associated with differential usage of COX-1 and COX-2. The COX-2-selective inhibitors NS-398 and nimesulide and the TXA2 receptor antagonist BMS 180,291 inhibited TNF-α- and Ang II-mediated increases in DNA content and' cell number by ≃95%. These findings suggest that a prostanoid derived from COX-2, possibly TXA2, may contribute to VSMC hyperplasia in vessel injury or pathophysiological conditions associated with elevated levels of either TNF- α or Ang II.