Cholesterol primes vascular smooth muscle to induce Ca2 sensitization mediated by a sphingosylphosphorylcholine-Rho-kinase pathway: possible role for membrane raft.
Hypercholesterolemia is a major risk factor involved in abnormal cardiovascular events. Rho-kinase-mediated Ca(2+) 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(2+) sensitization. Here we report the strong linkage between cholesterol and the Ca(2+) 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 beta-cyclodextrin resulted in a loss of membrane caveolin-1, a marker of cholesterol-enriched lipid raft, and inhibited the SPC-induced Ca(2+) 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(2+) 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.
Morikage
Noriyasu
N
Department of Molecular Physiology, Yamaguchi University School of Medicine, Ube, Japan.
Kishi
Hiroko
H
Sato
Masafumi
M
Guo
Fengling
F
Shirao
Satoshi
S
Yano
Takashi
T
Soma
Masaaki
M
Hamano
Kimikazu
K
Esato
Kensuke
K
Kobayashi
Sei
S
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002784:Cholesterol / Q000502:physiology*; D003331:Coronary Vessels / Q000473:pathology; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism*; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011817:Rabbits; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D054460:rho-Associated Kinases
D047908:Intracellular Signaling Peptides and Proteins; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; D002784:Cholesterol; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D013110:Sphingosine; D002118:Calcium