Ovarian cancer G protein-coupled receptor 1-dependent and -independent vascular actions to acidic pH in human aortic smooth muscle cells

Jin Peng Liu, Mayumi Komachi, Hideaki Tomura, Chihiro Mogi, Alatangaole Damirin, Masayuki Tobo, Mutsumi Takano, Hiromi Nochi, Koichi Tamoto, Koichi Sato, Fumikazu Okajima

研究成果: Article

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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, PGI2 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 Gq/11 protein. LPA remarkably enhanced, through the LPA1 receptor/Gi 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, PGI2 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 LPA1/Gi protein and OGR1/Gq/11 protein.

元の言語English
ページ(範囲)H731-H742
ジャーナルAmerican Journal of Physiology - Heart and Circulatory Physiology
299
発行部数3
DOI
出版物ステータスPublished - 1 9 2010

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