Published online before print July 6, 2006, doi: 10.1161/01.RES.0000235877.33682.e9
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Submitted on August 20, 2003
Revised on May 31, 2006
Accepted on June 27, 2006
Cholesterol Primes Vascular Smooth Muscle to Induce Ca2+ Sensitization Mediated by a Sphingosylphosphorylcholine-Rho-Kinase Pathway. Possible Role for Membrane Raft
Noriyasu Morikage ;
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.
* To whom correspondence should be addressed. 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 
-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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