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(Circulation Research. 2006;99:299.)
© 2006 American Heart Association, Inc.

Cellular Biology

Cholesterol Primes Vascular Smooth Muscle to Induce Ca² Sensitization Mediated by a Sphingosylphosphorylcholine–Rho-Kinase Pathway

Possible Role for Membrane Raft

Noriyasu Morikage, Hiroko Kishi, Masafumi Sato, Fengling Guo, Satoshi Shirao, Takashi Yano, Masaaki Soma, Kimikazu Hamano, Kensuke Esato, Sei Kobayashi

From the Department of Molecular Physiology (N.M., H.K., M. Sato, F.G., S.S., S.K.) and First Department of Surgery (N.M., K.H., K.E.), Yamaguchi University School of Medicine; and Mochida Pharmaceutical Co, Ltd (T.Y., M. Soma), Tokyo, Japan.

Correspondence to Sei Kobayashi, Department of Molecular Physiology, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan. E-mail seikoba{at}yamaguchi-u.ac.jp

Hypercholesterolemia is a major risk factor involved in abnormal cardiovascular events. Rho-kinase–mediated Ca²⁺ sensitization of vascular smooth muscle (VSM) plays a critical role in vasospasm and hypertension. We recently identified sphingosylphosphorylcholine (SPC) and Src family tyrosine kinase (Src-TK) as upstream mediators for the Rho-kinase–mediated Ca²⁺ sensitization. Here we report the strong linkage between cholesterol and the Ca²⁺ sensitization of VSM mediated by a novel SPC/Src-TK/Rho-kinase pathway in both humans and rabbits. The extent of the sensitization correlated well with the total cholesterol or low-density lipoprotein cholesterol levels in serum. However, an inverse correlation with the serum level of high-density lipoprotein cholesterol was observed, and a correlation with other cardiovascular risk factors was nil. When cholesterol-lowering therapy was given to patients and rabbits with hypercholesterolemia, the SPC-induced contractions diminished. Depletion of VSM cholesterol by ß-cyclodextrin resulted in a loss of membrane caveolin-1, a marker of cholesterol-enriched lipid raft, and inhibited the SPC-induced Ca²⁺ sensitization and translocation of Rho-kinase from cytosol to the cell membrane. Vasocontractions induced by membrane depolarization and by an adrenergic agonist were cholesterol-independent. Our data support the previously unreported concept that cholesterol potentiates the Ca²⁺ sensitization of VSM mediated by a SPC/Src-TK/Rho-kinase pathway, and are also compatible with a role for cholesterol-enriched membrane microdomain, a lipid raft. This process may play an important role in the development of abnormal vascular contractions in patients with hypercholesterolemia.

Key Words: Ca²⁺ sensitization • contraction • membrane lipid raft • Rho-kinase • sphingosylphosphorylcholine • vascular smooth muscle

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