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Pitavastatin, a 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitor, Blocks Vascular Smooth Muscle Cell Populated-Collagen Lattice Contraction

Kuzuya, Masafumi MD, PhD; Cheng, Xian Wu MD; Sasaki, Takeshi PhD; Tamaya-Mori, Norika PhD; Iguchi, Akihisa MD, PhD

Journal of Cardiovascular Pharmacology:
Original Articles
Abstract

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.

Author Information

From the Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Received for publication February 3, 2004; accepted February 27, 2004.

Reprints: Masafumi Kuzuya, Department of Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan (e-mail kuzuya@med.nagoya-u.ac.jp).

© 2004 Lippincott Williams & Wilkins, Inc.