title: IL-1β enhances vascular smooth muscle cell proliferation and migration via P2Y2 receptor-mediated RAGE expression and HMGB1 release.
abstract: Vascular smooth muscle cells (VSMCs) are the major cell type in blood vessel walls, and their proliferation and migration play important roles in the development of atherosclerosis. Recently, it has been reported that IL-1β mediates the inflammatory response through the upregulation of the P2Y2 receptor (P2Y2R). Thus, we examined the role of P2Y2R in IL-1β-mediated proliferation and migration of VSMCs and the underlying molecular mechanisms. VSMCs were pretreated with IL-1β for 24h to upregulate P2Y2R expression. The cells were then stimulated with UTP or ATP for the indicated times, and cell proliferation and migration and the related signaling pathways were examined. The equipotent P2Y2R agonists ATP and UTP enhanced proliferation, RAGE expression and HMGB1 secretion in IL-1β-pretreated VSMCs. Additionally, pretreatment with IL-1β enhanced UTP-mediated VSMC migration and MMP-2 release, but these effects were not observed in the P2Y2R-siRNA- or RAGE-siRNA-transfected VSMCs. Next, the signaling molecules involved in P2Y2R-mediated cell proliferation and migration were determined. The ERK, AKT, PKC, Rac-1 and ROCK2 pathways were involved in UTP-induced cell proliferation and migration, MMP-2 and HMGB1 secretion and RAGE expression in the IL-1β-pretreated VSMCs. UTP induced the phosphorylation of ERK, AKT and PKC and the translocation of Rac-1 and ROCK2 from cytosol to membrane as well as stress fiber formation, which were markedly increased in the IL-1β-pretreated VSMCs but not in the P2Y2R-siRNA-transfected VSMCs. These results demonstrate that pro-inflammatory cytokines associated with atherosclerosis, such as IL-1β, can accelerate the process of atherosclerosis through the upregulation of P2Y2R.
authors.affiliation: Department of Pharmacology, School Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 660-290, Republic of Korea.
authors.forename: So Young
authors.initials: SY
authors.lastname: Eun
authors.affiliation: Department of Pharmacology, School Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 660-290, Republic of Korea.
authors.forename: Young Shin
authors.initials: YS
authors.lastname: Ko
authors.affiliation: Department of Pharmacology, School Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 660-290, Republic of Korea.
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Park
authors.affiliation: Department of Pharmacology, School Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 660-290, Republic of Korea.
authors.forename: Ki Churl
authors.initials: KC
authors.lastname: Chang
authors.affiliation: Department of Pharmacology, School Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 660-290, Republic of Korea. Electronic address: hyejungkim@gnu.ac.kr.
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology*; D002478:Cells, Cultured; D024243:HMGB1 Protein / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D058473:Receptors, Purinergic P2Y2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: C000593874:Ager protein, rat; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D053583:Interleukin-1beta; D000067759:Receptor for Advanced Glycation End Products; D058473:Receptors, Purinergic P2Y2
keywords: HMGB1; IL-1β; P2Y(2) nucleotide receptor; Proliferation; RAGE; Vascular smooth muscle cells