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.