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(Circulation Research. 2002;91:953.)
© 2002 American Heart Association, Inc.

Integrative Physiology

Involvement of Src Family Protein Tyrosine Kinases in Ca²⁺ Sensitization of Coronary Artery Contraction Mediated by a Sphingosylphosphorylcholine-Rho-Kinase Pathway

Fumiaki Nakao, Sei Kobayashi, Kimiko Mogami, Yoichi Mizukami, Satoshi Shirao, Saori Miwa, Natsuko Todoroki-Ikeda, Masaaki Ito, Masunori Matsuzaki

From the Departments of Cardiovascular Medicine (F.N., M.M.) and Molecular Physiology (F.N., S.K., K.M., Y.M., S.S., S.M., N.T.-I.), Yamaguchi University School of Medicine, Yamaguchi, Japan; and the First Department of Internal Medicine (M.I.), Mie University School of Medicine, Mie, Japan.

Correspondence to Dr Sei Kobayashi, Dept 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

We recently reported that sphingosylphosphorylcholine (SPC) is a novel messenger for Rho-kinase–mediated Ca²⁺ sensitization of vascular smooth muscle (VSM) contraction. Subcellular localization and kinase activity of Src family protein kinases (SrcPTKs), except for c-Src, is controlled by a reversible S-palmitoylation, an event inhibited by eicosapentaenoic acid (EPA). We examined the possible involvement of SrcPTKs in SPC-induced Ca²⁺ sensitization and effects of EPA. We used porcine coronary VSM and rat aortic VSM cells (VSMCs) in primary culture. An SrcPTKs inhibitor, PP1, and EPA inhibited SPC-induced contraction, concentration-dependently, without affecting [Ca²⁺]_i levels and the Ca²⁺-dependent contraction induced by high K⁺ depolarization. A digitized immunocytochemical analysis in VSMCs revealed that SPC induced translocation of Fyn, but not of c-Src, from the cytosol to the cell membrane, an event abolished by EPA. Translocation of Rho-kinase from the cytosol to the cell membrane by SPC was also inhibited by EPA and PP1. The SPC-induced activation of SrcPTKs was blocked by EPA and PP1, but not by Y27632, an Rho-kinase inhibitor. Rho-kinase–dependent phosphorylation of myosin phosphatase induced by SPC was inhibited by EPA, PP1, and Y27632. Translocation and activation of SrcPTKs, including Fyn, play an important role in Ca²⁺ sensitization of VSM contractions mediated by a SPC-Rho-kinase pathway.

Key Words: sphingosylphosphorylcholine • Ca²⁺ sensitization • Src family protein tyrosine kinase • eicosapentaenoic acid • S-palmitoylation

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