(Hypertension. 2000;35:68.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Induction of Cyclooxygenase-2 by Angiotensin II in Cultured Rat Vascular Smooth Muscle Cells
From the Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tenn.
Correspondence to Tadashi Inagami, PhD, Department of Biochemistry, Vanderbilt University School of Medicine, 663 Light Hall, Nashville, TN 37232-0146. E-mail inagamit{at}ctrvax.vanderbilt.edu
Abstract—Angiotensin II (Ang II) stimulates the release of prostaglandins (PGs) in various cells and tissues. Recently, cyclooxygenase-2 (COX-2) emerged as a new key regulator for PG synthesis. In the present study, we investigated whether Ang II regulates COX-2 expression in cultured rat vascular smooth muscle cells (VSMCs). Ang II markedly increased the expression of COX-2 mRNA in a time- and dose-dependent manner. This effect was completely blocked by the Ang II type 1 receptor antagonist losartan but not by the Ang II type 2 receptor antagonist PD123319. The p42/44 mitogen-activated protein kinase (MAPK) kinase-1 inhibitor PD98059 and the p38 MAPK inhibitor SB203580 significantly suppressed Ang II–induced COX-2 mRNA and protein expression. Ang II did not increase transcription of the COX-2 gene, as examined with a COX-2 promoter/luciferase chimeric plasmid construct. Instead, it suppressed the degradation of COX-2 mRNA. PD98059 and SB203580 markedly enhanced the decay of COX-2 mRNA induced by Ang II, implying that p42/44 and p38 MAPK activated by Ang II play a role in the regulation of COX-2 through stabilization of its mRNA. The COX-2–specific inhibitor NS-398 attenuated Ang II–stimulated DNA and protein synthesis, as well as PGE2 production by VSMCs. These results suggest that Ang II regulates COX-2 expression and PG production and modulates cell proliferation through MAPK-mediated signaling pathways in rat VSMCs.
Key Words: angiotensin II • cyclooxygenase 2 • protein kinases • muscle, smooth, vascular
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