title: PAF enhances MMP-2 production in rat aortic VSMCs via a β-arrestin2-dependent ERK signaling pathway.
abstract: Platelet-activating factor (PAF), 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine, is a potent phospholipid mediator and has been reported to be localized in atherosclerotic plaque. However, its role in the progression of atherosclerosis remains unclear. In the present study, we investigated the role of PAF in the production of matrix metalloproteinase (MMP) in primary vascular smooth muscle cells (VSMCs). When rat aortic primary VSMCs were stimulated with PAF (1 nmol/l), the expressions of MMP-2 mRNA and protein, but not of MMP-9, were significantly increased, and these upregulations were markedly attenuated by inhibiting extracellular signal-regulated kinases (ERKs) using molecular and pharmacological inhibitors, but not by using inhibitors of p38 mitogen-activated protein kinase or c-Jun N-terminal kinase. Likewise, ERK phosphorylation was markedly enhanced in PAF-stimulated VSMCs, and this was attenuated by WEB2086, but not by EGF receptor inhibitor, demonstrating the specificity of PAF receptor (PAFR) in PAF-induced ERK phosphorylation. In immunofluorescence studies, β-arrestin2 in PAF-stimulated VSMCs colocalized with PAFR and phosphorylated ERK (P-ERK). Coimmunoprecipitation results suggest that β-arrestin2-bound PAFRs existed as a complex with P-ERK. In addition, PAF-induced ERK phosphorylation and MMP-2 production were significantly attenuated by β-arrestin2 depletion. Taken together, the study shows that PAF enhances MMP-2 production in VSMCs via a β-arrestin2-dependent ERK signaling pathway.
authors.affiliation: Departments of Pharmacology and Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Yun H
authors.initials: YH
authors.lastname: Kim
authors.forename: Seung J
authors.initials: SJ
authors.lastname: Lee
authors.forename: Kyo W
authors.initials: KW
authors.lastname: Seo
authors.forename: Jin U
authors.initials: JU
authors.lastname: Bae
authors.forename: So Y
authors.initials: SY
authors.lastname: Park
authors.forename: Eun K
authors.initials: EK
authors.lastname: Kim
authors.forename: Sun S
authors.initials: SS
authors.lastname: Bae
authors.forename: Jae H
authors.initials: JH
authors.lastname: Kim
authors.forename: Chi D
authors.initials: CD
authors.lastname: Kim
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D019390:Arrestins / Q000378:metabolism*; D002478:Cells, Cultured; D004790:Enzyme Induction; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology*; D010766:Phosphorylation; D010972:Platelet Activating Factor / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; C039351:platelet activating factor receptor; D048049:Extracellular Signal-Regulated MAP Kinases; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat
keywords: extracellular signal-regulated kinase; matrix metalloproteinase-2; platelet-activating factor; platelet-activating factor receptor; β-arrestin2
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