Pitavastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, blocks vascular smooth muscle cell populated-collagen lattice contraction.
Constrictive arterial remodeling plays a major role in lumen narrowing following angioplasty. We investigated the effect of pitavastatin, a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor, on vascular smooth muscle cell (SMC)-populated collagen lattice contraction, an in vitro model of vascular contraction. Type I collagen gel contraction by SMCs, which are cultured in collagen gel, was used as a model of vascular remodeling. Pitavastatin pretreatment inhibited 10% serum- or platelet-derived growth factor-BB (PDGF)-induced SMC-mediated collagen lattice contraction in a concentration-dependent manner. The effect of pitavastatin was prevented by mevalonate or geranylgeranyl pyrophosphate, but not by squalene, a precursor of cholesterol, or farnesyl pyrophosphate. The serum- or PDGF-induced SMC-mediated collagen gel contraction was inhibited by GGTI-298, a geranylgeranyltransferase inhibitor, C3 exoenzyme, an inhibitor of Rho, or Y27634, a Rho kinase inhibitor, but not by FTI-277, a farnesyltransferase inhibitor. Serum or PDGF treatment increased the stress fiber organization in SMCs, which was blocked by the pitavastatin pretreatment. Pitavastatin had no effect on the serum- and PDGF-induced lamelliopodia extension of SMC. These results may suggest that pitavastatin attenuates SMC-mediated collagen gel contraction probably via an inhibition of geranylgeranylated Rho protein and a disruption of actin cytoskeletal reorganization.
Kuzuya
Masafumi
M
Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan. kuzuya@med.nagoya-u.ac.jp
Cheng
Xian Wu
XW
Sasaki
Takeshi
T
Tamaya-Mori
Norika
N
Iguchi
Akihisa
A
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology; D002417:Cattle; D002478:Cells, Cultured; D024042:Collagen Type I / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D011804:Quinolines / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
D024042:Collagen Type I; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011804:Quinolines; C108475:pitavastatin