Inhibition of sphingosine kinase 1 ameliorates angiotensin ii-induced hypertension and inhibits transmembrane calcium entry via store-operated calcium channel

Parker C. Wilson, Wayne R. Fitzgibbon, Sara M. Garrett, Ayad A. Jaffa, Louis M. Luttrell, Michael W. Brands, Hesham M. El-Shewy

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Angiotensin II (AngII) plays a critical role in the regulation of vascular tone and blood pressure mainly via regulation of Ca2+ mobilization. Several reports have implicated sphingosine kinase 1 (SK1)/sphingosine 1-phosphate (S1P) in the mobilization of intracellular Ca2+ through a yet-undefined mechanism. Here we demonstrate that AngII-induces biphasic calcium entry in vascular smooth muscle cells, consisting of an immediate peak due to inositol tris-phosphate-dependent release of intracellular calcium, followed by a sustained transmembrane Ca2+ influx through store-operated calcium channels (SOCs). Inhibition of SK1 attenuates the second phase of transmembrane Ca2+ influx, suggesting a role for SK1 in AngII-dependent activation of SOC. Intracellular S1P triggers SOC-dependent Ca2+ influx independent of S1P receptors, whereas external application of S1P stimulated S1P receptor-dependent Ca2+ influx that is insensitive to inhibitors of SOCs, suggesting that the SK1/S1P axis regulates store-operated calcium entry via intracellular rather than extracellular actions. Genetic deletion of SK1 significantly inhibits both the acute hypertensive response to AngII in anaesthetized SK1 knockout mice and the sustained hypertensive response to continuous infusion of AngII in conscious animals. Collectively these data implicate SK1 as the missing link that connects the angiotensin AT1A receptor to transmembrane Ca2+influx and identify SOCs as a potential intracellular target for SK1.

Original languageEnglish (US)
Pages (from-to)896-908
Number of pages13
JournalMolecular Endocrinology
Volume29
Issue number6
DOIs
StatePublished - Jun 1 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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