Angiotensin II increases expression of cyclooxygenase-2: implications for the function of vascular smooth muscle cells.
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.
Hu
Zhuo-Wei
ZW
Geriatric Research, Education, and Clinical Center, Veterans Affairs Palo Alto Health Care System, GRECC 182B, 3801 Miranda Avenue, Palo Alto, CA 94304, USA. huzhwei@stanford.edu
Kerb
Reinhold
R
Shi
Xiao-You
XY
Wei-Lavery
Tzuping
T
Hoffman
Brian B
BB
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015152:Blotting, Northern; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004247:DNA / Q000096:biosynthesis; D004586:Electrophoresis; D004797:Enzyme-Linked Immunosorbent Assay; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D007527:Isoenzymes / Q000096:biosynthesis*; D008565:Membrane Proteins; D008938:Mitosis / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D011233:Precipitin Tests; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D011453:Prostaglandins / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013268:Stimulation, Chemical; D014157:Transcription Factors / Q000819:agonists
D007527:Isoenzymes; D008565:Membrane Proteins; D011453:Prostaglandins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000804:Angiotensin II; D004247:DNA; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases