In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 91, No. 2 ( 2002-07-26), p. 112-119
Abstract:
Although recent investigations have suggested that a Rho-kinase–mediated Ca 2+ 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 Ca 2+ sensitization in pig coronary arteries. The purpose of this present study was to examine the possible mediation of SPC in Ca 2+ 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 (EC 50 =3.0 μmol/L) contraction, without [Ca 2+ ] i elevation. In membrane-permeabilized MCA, SPC induced Ca 2+ sensitization even in the absence of added GTP, which is required for activation of G-proteins coupled to membrane receptors. The SPC-induced Ca 2+ 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 Ca 2+ -independent contraction induced by phorbol ester. In contrast, phorbol ester–induced Ca 2+ 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 Ca 2+ 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.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/01.RES.0000026057.13161.42
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2002
detail.hit.zdb_id:
1467838-X
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