title: Pitavastatin inhibits vascular smooth muscle cell proliferation by inactivating extracellular signal-regulated kinases 1/2.
abstract: We recently reported that lysophosphatidylcholine (lysoPC) acts on vascular smooth muscle cells ( VSMCs ) to produce a mitogenic response through the activation of extracellular signal-regulated kinases 1/2 (ERK1/2). In this study, we examined the role of HMG-CoA reductase inhibitors on lysoPC-induced VSMC proliferation. Pitavastatin, a new HMG-CoA reductase inhibitor, suppressed lysoPC-induced DNA synthesis in primary cultured rat VSMCs. Since lysoPC-induced ERK1/2 activation contributes to smooth muscle cell proliferation, we explored the effect of pitavastatin on ERK1/2 activation. Pitavastatin inhibited lysoPC-induced ERK1/2 phosphorylation and ERK1/2 activation. The other HMG-CoA reductase inhibitors, atrovastatin and fluvastatin, also inhibited lysoPC-induced ERK1/2 phosphorylation. Pitavastatin also inhibited lysoPC-induced c-fos mRNA expression. To gain insight into the mechanism of the inhibitory effect of pitavastatin on ERK1/2 activation by lysoPC, we examined the role of the mevalonate pathways. Mevalonate and farnesylpyrophosphate reduced the inhibition of ERK1/2 phosphorylation by pitavastatin. These studies demonstrate that pitavastatin may inhibit lysoPC-induced VSMC proliferation, at least in part, by inactivating ERK1/2, which is linked to mevalonate metabolism.
authors.affiliation: Department of Endocrinology and Diabetes, Yokohama City University Medical Center, Yokohama, Japan. yamakat@urahp.yokohama-cu.ac.jp
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamakawa
authors.forename: Shun-ichi
authors.initials: S
authors.lastname: Tanaka
authors.forename: Junzo
authors.initials: J
authors.lastname: Kamei
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Kadonosono
authors.forename: Kenji
authors.initials: K
authors.lastname: Okuda
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015151:Immunoblotting; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011804:Quinolines; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C108475:pitavastatin