Published online before print June 13, 2002, doi: 10.1161/01.RES.0000026057.13161.42
© 2002 American Heart Association, Inc.
Molecular Medicine |
Sphingosylphosphorylcholine Is a Novel Messenger for Rho-Kinase–Mediated Ca2+ Sensitization in the Bovine Cerebral Artery
Unimportant Role for Protein Kinase C
From the Departments of Molecular Physiology (S.S., M. Sato, S.M., F.N., T.K., N.T.-I., K.M., Y.M., S. Kobayashi) and Neurosurgery (S.S., S. Kashiwagi, T.K., M. Suzuki), Yamaguchi University School of Medicine, Ube, Japan; and the Research Center of Mochida Pharmaceutical Co, LTD (S. Kuriyama, K.H.), Gotemba, Japan.
Correspondence to Sei Kobayashi, MD, PhD, Dept of Molecular Physiology, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi, Ube 755-8505, Japan. E-mail seikoba{at}yamaguchi-u.ac.jp
Although recent investigations have suggested that a Rho-kinase–mediated Ca2+ sensitization of vascular smooth muscle contraction plays a critical role in the pathogenesis of cerebral and coronary vasospasm, the upstream of this signal transduction has not been elucidated. In addition, the involvement of protein kinase C (PKC) may also be related to cerebral vasospasm. We recently reported that sphingosylphosphorylcholine (SPC), a sphingolipid, induces Rho-kinase–mediated Ca2+ sensitization in pig coronary arteries. The purpose of this present study was to examine the possible mediation of SPC in Ca2+ sensitization of the bovine middle cerebral artery (MCA) and the relation to signal transduction pathways mediated by Rho-kinase and PKC. In intact MCA, SPC induced a concentration-dependent (EC50=3.0 µmol/L) contraction, without [Ca2+]i elevation. In membrane-permeabilized MCA, SPC induced Ca2+ sensitization even in the absence of added GTP, which is required for activation of G-proteins coupled to membrane receptors. The SPC-induced Ca2+ sensitization was blocked by a Rho-kinase inhibitor (Y-27632) and a dominant-negative Rho-kinase, but not by a pseudosubstrate peptide for conventional PKC, which abolished the Ca2+-independent contraction induced by phorbol ester. In contrast, phorbol ester–induced Ca2+ sensitization was resistant to a Rho-kinase inhibitor and a dominant-negative Rho-kinase. In primary cultured vascular smooth muscle cells, SPC induced the translocation of cytosolic Rho-kinase to the cell membrane. We propose that SPC is a novel messenger for Rho-kinase–mediated Ca2+ sensitization of cerebral arterial smooth muscle and, therefore, may play a pivotal role in the pathogenesis of abnormal contraction of the cerebral artery such as vasospasm. The SPC/Rho-kinase pathway functions independently of the PKC pathway.
Key Words: vasospasm • sphingolipid • protein kinase C • Rho-kinase • membrane permeabilization
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