Cholesterol Primes Vascular Smooth Muscle to Induce Ca ² Sensitization Mediated by a Sphingosylphosphorylcholine–Rho-Kinase Pathway

Abstract

Abstract-Hypercholesterolemia is a major risk factor involved in abnormal cardiovascular events. Rho-kinase-mediated Ca 2ϩ 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 Ca 2ϩ sensitization. Here we report the strong linkage between cholesterol and the Ca 2ϩ 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 Ca 2ϩ 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 Ca 2ϩ 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: Ca 2ϩ sensitization Ⅲ contraction Ⅲ membrane lipid raft Ⅲ Rho-kinase Ⅲ sphingosylphosphorylcholine Ⅲ vascular smooth muscle A bnormal vascular contraction as a result of Ca 2ϩ sensitization of vascular smooth muscles (VSMs) has attracted attention as a cause of hypertension and vasospasm. 1 Kureishi et al showed that constitutively active Rho-kinase applied to the cytosol of permeabilized VSM induced Ca 2ϩ sensitization and increased myosin light chain phosphorylation through a mechanism that is independent of a Ca 2ϩ -dependent myosin light chain kinase pathway. 2 In addition, the Rho-kinase blocker Y27632 cures hypertension in rats without affecting normal blood pressure, 3 and it also inhibits vasospasm of coronary arteries in a porcine model. 4 However, the mechanism by which Rho-kinase-mediated Ca 2ϩ sensitization of VSM is triggered in cardiovascular diseases has not been evident.Hyperlipidemia is a major risk factor for abnormal cardiovascular events. Evidence for this is provided by the J-shaped curve showing a strong relationship between serum cholesterol levels and the relative risk for coronary disease 5-7 (see also Figure I in the online data supplement, available at http://circres.ahajournals.org). Atheromatous plaques may be involved in cardiovascular events, 8,9 but the ext...

Rho-Kinase Inhibition Improves Ischemic Perfusion Deficit in Hyperlipidemic Mice

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Cold-induced cutaneous vasoconstriction is mediated by Rho kinase in vivo in human skin

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Rho kinase in the regulation of cell death and survival

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