Angiotensin II increases expression of cyclooxygenase-2: implications for the function of vascular smooth muscle cells

J Pharmacol Exp Ther. 2002 Nov;303(2):563-73. doi: 10.1124/jpet.102.037705.

Abstract

In vascular smooth muscle, increased expression of cyclooxygenase-2 (COX-2) has emerged as an important mechanism for regulation of prostanoid synthesis influenced by vessel injury, cytokines, and growth factors. We have investigated how COX-2 participates in angiotensin II (ANG II)-mediated cell responses in cultured human vascular smooth muscle cells (VSMCs). ANG II type 1 (AT1) receptors induce increased accumulation of COX-2, both at the mRNA and protein levels. ANG II increased transcription of the COX-2 gene; also, nuclear extracts from stimulated cells had increased NF-kappa B binding to its DNA consensus sequence. ANG II-induced COX-2 expression was markedly blunted by inhibition of mitogen-activated protein kinase. Furthermore, the ANG II-induced increase in COX-2 protein abundance was attenuated by both the peroxisome proliferator-activated receptor alpha (PPARalpha) activator Wy-14,643 [pyrinixic acid; 4-chloro-6-(2,3-xylidino)-2-pyrimidinyl) thioacetic acid] and the PPARgamma activator 15d-PGJ2 (15-deoxy-Delta(12-14)-prostaglandin J2). Not only did ANG II increase COX-2 expression and prostaglandin synthesis, ANG II-stimulated DNA synthesis and cell migration were dependent on COX-2 activity. PPARalpha and PPARgamma activators inhibited ANG II-stimulated DNA synthesis and cell migration. These results suggest that ANG II enhances COX-2 expression at the transcription level; also, COX-2 activity plays an important role in mediating ANG II- induced proliferation and migration of VSMCs, suggesting the possibility of magnification of ANG II effects over time due to the induction of COX-2 expression. These results also demonstrate that both the alpha and gamma type of PPAR activators inhibit COX-2 expression induced by angiotensin II in VSMCs which may have therapeutic significance in vascular diseases.

Publication types

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

MeSH terms

  • Angiotensin II / antagonists & inhibitors
  • Angiotensin II / pharmacology*
  • Blotting, Northern
  • Cell Division / drug effects
  • Cell Movement / drug effects
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Cyclooxygenase 2
  • DNA / biosynthesis
  • Electrophoresis
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Regulation, Enzymologic / drug effects
  • Humans
  • Immunoblotting
  • Isoenzymes / biosynthesis*
  • Membrane Proteins
  • Mitosis / drug effects
  • Muscle, Smooth, Vascular / chemistry
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / enzymology*
  • Precipitin Tests
  • Prostaglandin-Endoperoxide Synthases / biosynthesis*
  • Prostaglandins / metabolism
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stimulation, Chemical
  • Transcription Factors / agonists

Substances

  • Isoenzymes
  • Membrane Proteins
  • Prostaglandins
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • Angiotensin II
  • DNA
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases