RT Journal Article
SR Electronic
T1 Angiotensin II Increases Expression of Cyclooxygenase-2: Implications for the Function of Vascular Smooth Muscle Cells
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 563
OP 573
DO 10.1124/jpet.102.037705
VO 303
IS 2
A1 Hu, Zhuo-Wei
A1 Kerb, Reinhold
A1 Shi, Xiao-You
A1 Wei-Lavery, Tzuping
A1 Hoffman, Brian B.
YR 2002
UL http://jpet.aspetjournals.org/content/303/2/563.abstract
AB 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-κ 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 α (PPARα) activator Wy-14,643 [pyrinixic acid; 4-chloro-6-(2,3-xylidino)-2-pyrimidinyl) thioacetic acid] and the PPARγ activator 15d-PGJ2 (15-deoxy-Δ12–14-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. PPARα and PPARγ 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 α and γ type of PPAR activators inhibit COX-2 expression induced by angiotensin II in VSMCs which may have therapeutic significance in vascular diseases. U.S. Government