血管平滑筋異常収縮のシグナル伝達におけるコレステロールおよび膜ラフトの重要性

抄録

Rho-kinase (ROK)-mediated Ca²⁺-sensitization of vascular smooth muscle (VSM) contraction plays a critical role in abnormal VSM contraction. We previously found that sphingosylphosphorylcholine (SPC) induces the ROK-mediated Ca²⁺-sensitization, dependently on cholesterol in serum and VSM tissue and through the activation of Src family tyrosine kinases (Src-TKs). In this study, we examined the involvement of membrane rafts, a cholesterol-enriched membrane microdomain, in the SPC/ROK-mediated Ca²⁺-sensitization. Immunocytochemistry and membrane fractionation revealed that SPC induced the translocations of Fyn, a member of Src-TKs, and ROK from cytosol to membrane rafts, which were labeled with caveolin-1 and cholera toxin subunit B. In addition, β-cyclodextrin, which selectively deprived VSM membrane of cholesterol and thereby removed caveolin-1 from membrane rafts, inhibited the SPC-induced translocation of Fyn and ROK and VSM contraction, without affecting Ca²⁺-induced contraction. In contrast, eicosapentaenoic acid (EPA), an inhibitor of Src-TKs translocation, inhibited the SPC-induced translocation of Fyn and ROK without affecting the localization of caveolin-1. Moreover, EPA selectively abolished the SPC-induced Ca²⁺-sensitization, without affecting the Ca²⁺-induced contraction. These findings suggest that membrane rafts play a pivotal role in abnormal VSM contraction. [J Physiol Sci. 2008;58 Suppl:S52]