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.
Highlights
Platelet-activating factor (PAF), 1-O-alkyl-2-acetylsn-glycero-3-phosphocholine, is a potent phospholipid mediator and has been reported to be localized in atherosclerotic plaque
When vascular smooth muscle cell (VSMC) were stimulated with PAF (1 nmol/l), matrix metalloproteinase (MMP)-2 mRNA, and MMP-2 protein, productions in passage 1 (P1) and passage 5 (P5) VSMCs were significantly increased, whereas MMP-9 showed little change (Fig. 1C–F)
The present study identifies the signal pathways by which PAF enhances MMP-2 production in rat aortic primary VSMCs
Summary
Platelet-activating factor (PAF), 1-O-alkyl-2-acetylsn-glycero-3-phosphocholine, is a potent phospholipid mediator and has been reported to be localized in atherosclerotic plaque. We investigated the role of PAF in the production of matrix metalloproteinase (MMP) in primary vascular smooth muscle cells (VSMCs). In immunofluorescence studies, -arrestin in PAF-stimulated VSMCs colocalized with PAFR and phosphorylated ERK (P-ERK). The study shows that PAF enhances MMP-2 production in VSMCs via a -arrestin2-dependent ERK signaling pathway.— Kim, Y. D. Kim. PAF enhances MMP-2 production in rat aortic VSMCs via a -arrestin2dependent ERK signaling pathway. Numerous G protein-coupled receptors (GPCRs) activate mitogen-activated protein kinase (MAPK) after specific agonist stimulation [6,7,8], and after agonist binding, 7TMR phosphorylates MAPKs via the classical G protein-induced synthesis of various second messengers, which include Ca2+, or via nonclassical pathways by modulating novel effectors independent of G protein [9].
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