Journal
CIRCULATION RESEARCH
Volume 86, Issue 8, Pages 906-914Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.86.8.906
Keywords
angiotensin II; tumor necrosis factor-alpha; vascular smooth muscle cells; cyclooxygenase-2
Funding
- NHLBI NIH HHS [R01HL56423] Funding Source: Medline
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Tumor necrosis factor-alpha(TNF-alpha) and angiotensin II (Ang II) induced a transient increase in vascular smooth muscle cell (VSMC) cyclooxygenase-3 (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 approximate to 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. Tn 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 EMS 180,291 inhibited TNF-alpha- and Ang II-mediated increases in DNA content and cell number by approximate to 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.
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