title: Ovarian cancer G protein-coupled receptor 1-dependent and -independent vascular actions to acidic pH in human aortic smooth muscle cells.
abstract: Atherosclerosis is a chronic inflammation disease characterized by acidic micromilieu and the accumulation of numerous bioactive lipid mediators, such as lysophosphatidic acid (LPA) and prostaglandins, in the atherosclerotic lesion. Chronic acidification induced various effects on vascular smooth muscle cells, but the molecular mechanisms underlying these effects remain unknown. In this study, we examine the role of proton-sensing ovarian cancer G protein-coupled receptor 1 (OGR1) in extracellular acidification-induced regulation of cyclooxygenase (COX)-2 induction, PGI(2) production, MAPK phosphatase (MKP)-1 expression, and plasminogen activator inhibitor (PAI)-1 expression and proliferation in human aortic smooth muscle cells (AoSMCs). Experiments with knockdown with small interfering RNA specific to OGR1 and specific inhibitors for G proteins showed that acidification-induced COX-2 expression, PGI(2) production, and MKP-1 expression, but not PAI-1 expression and inhibition of proliferation, were dependent on OGR1 and mainly mediated by G(q/11) protein. LPA remarkably enhanced, through the LPA(1) receptor/G(i) protein, the OGR1-mediated vascular actions to acidic pH. In conclusion, acidic pH-induced vascular actions of AoSMCs can be dissected to OGR1-dependent and -independent pathways: COX-2 expression, PGI(2) production, and MKP-1 expression are mediated by OGR1, but PAI-1 expression and inhibition of proliferation are not. LPA, which is usually thought to be a proatherogenic lipid mediator, may exert antiatherogenic actions under acidic micromilieu through cross-talk between LPA(1)/G(i) protein and OGR1/G(q/11) protein.
authors.affiliation: Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.
authors.forename: Jin-Peng
authors.initials: JP
authors.lastname: Liu
authors.forename: Mayumi
authors.initials: M
authors.lastname: Komachi
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tomura
authors.forename: Chihiro
authors.initials: C
authors.lastname: Mogi
authors.forename: Alatangaole
authors.initials: A
authors.lastname: Damirin
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tobo
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Takano
authors.forename: Hiromi
authors.initials: H
authors.lastname: Nochi
authors.forename: Koichi
authors.initials: K
authors.lastname: Tamoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Sato
authors.forename: Fumikazu
authors.initials: F
authors.lastname: Okajima
mesh_terms: D000704:Analysis of Variance; D001011:Aorta / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: C486281:GPR68 protein, human; D017395:Plasminogen Activator Inhibitor 1; D043562:Receptors, G-Protein-Coupled; D011464:Epoprostenol; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; D054638:Dual Specificity Phosphatase 1