title: Ceramide 1-phosphate induces neointimal formation via cell proliferation and cell cycle progression upstream of ERK1/2 in vascular smooth muscle cells.
abstract: Ceramide 1-phosphate (C1P) is a novel bioactive sphingolipid formed by ceramide kinase (CERK)-catalyzed phosphorylation of ceramide. It has been implicated in the regulation of such vital pathophysiological functions as phagocytosis and inflammation, but there have been no reports ascribing a biological function to CERK in vascular disorders. Here the potential role of CERK/C1P in neointimal formation was investigated using rat aortic vascular smooth muscle cells (VSMCs) in primary culture and a rat carotid injury model. Exogenous C8-C1P stimulated cell proliferation, DNA synthesis, and cell cycle progression of rat aortic VSMCs in primary culture. In addition, wild-type CERK-transfected rat aortic VSMCs induced a marked increase in rat aortic VSMC proliferation and [(3)H]-thymidine incorporation when compared to empty vector transfectant. C8-C1P markedly activated extracellular signal-regulated kinase 1 and 2 (ERK1/2) within 5min, and the activation could be prevented by U0126, a MEK inhibitor. Also, K1, a CERK inhibitor, decreased the ERK1/2 phosphorylation and cell proliferation on platelet-derived growth factor (PDGF)-stimulated rat aortic VSMCs. CERK expression and C1P levels were found to be potently increased during neointimal formation using a rat carotid injury model. However, ceramide levels decreased during the neointimal formation process. These findings suggest that C1P can induce neointimal formation via cell proliferation through the regulation of the ERK1/2 protein in rat aortic VSMCs and that CERK/C1P may regulate VSMC proliferation as an important pathogenic marker in the development of cardiovascular disorders.
authors.affiliation: Division of Biological Science and Technology, College of Science and Technology, Yonsei University, Wonju 220-710, Republic of Korea. ktj@yonsei.ac.kr
authors.forename: Tack-Joong
authors.initials: TJ
authors.lastname: Kim
authors.forename: Yeo-Jin
authors.initials: YJ
authors.lastname: Kang
authors.forename: Yong
authors.initials: Y
authors.lastname: Lim
authors.forename: Hyoung-Woo
authors.initials: HW
authors.lastname: Lee
authors.forename: Kiho
authors.initials: K
authors.lastname: Bae
authors.forename: Youn-Sun
authors.initials: YS
authors.lastname: Lee
authors.forename: Jae-Myung
authors.initials: JM
authors.lastname: Yoo
authors.forename: Hwan-Soo
authors.initials: HS
authors.lastname: Yoo
authors.forename: Yeo-Pyo
authors.initials: YP
authors.lastname: Yun
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002518:Ceramides / Q000494:pharmacology*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D058426:Neointima / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002518:Ceramides; C065576:ceramide 1-phosphate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3