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

Circ Res. 2000 Apr 28;86(8):906-14. doi: 10.1161/01.res.86.8.906.

Abstract

Tumor necrosis factor-alpha (TNF-alpha) 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-alpha or Ang II; mRNA accumulation peaked at 2 hours and decreased to control levels by approximately 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-alpha or Ang II. Both the increase in COX-2 mRNA accumulation and protein expression in response to either TNF-alpha or Ang II were inhibited by the mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor PD098059. In addition, the AT(1)-selective receptor antagonist losartan attenuated the Ang II-mediated increase in COX-2 mRNA accumulation; the AT(2)-selective antagonist PD123319 had no effect. Prostacyclin I(2) synthesis was tightly coupled to expression of COX-2, whereas prostaglandin E(2) and thromboxane A(2) (TXA(2)) synthesis may be associated with differential usage of COX-1 and COX-2. The COX-2-selective inhibitors NS-398 and nimesulide and the TXA(2) receptor antagonist BMS 180,291 inhibited TNF-alpha- and Ang II-mediated increases in DNA content and cell number by approximately 95%. These findings suggest that a prostanoid derived from COX-2, possibly TXA(2), may contribute to VSMC hyperplasia in vessel injury or pathophysiological conditions associated with elevated levels of either TNF-alpha or Ang II.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Angiotensin II / pharmacology*
  • Animals
  • Cell Division / drug effects
  • Cell Division / physiology
  • Cells, Cultured
  • Cyclooxygenase 2
  • Isoenzymes / physiology*
  • Male
  • Muscle, Smooth, Vascular / cytology*
  • Muscle, Smooth, Vascular / physiology*
  • Prostaglandin-Endoperoxide Synthases / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Vasoconstrictor Agents / pharmacology*

Substances

  • Isoenzymes
  • Tumor Necrosis Factor-alpha
  • Vasoconstrictor Agents
  • Angiotensin II
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases