title: Inhibition of Sphingosine Kinase 1 Ameliorates Angiotensin II-Induced Hypertension and Inhibits Transmembrane Calcium Entry via Store-Operated Calcium Channel.
abstract: Angiotensin II (AngII) plays a critical role in the regulation of vascular tone and blood pressure mainly via regulation of Ca(2+) mobilization. Several reports have implicated sphingosine kinase 1 (SK1)/sphingosine 1-phosphate (S1P) in the mobilization of intracellular Ca(2+) 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 Ca(2+) influx through store-operated calcium channels (SOCs). Inhibition of SK1 attenuates the second phase of transmembrane Ca(2+) influx, suggesting a role for SK1 in AngII-dependent activation of SOC. Intracellular S1P triggers SOC-dependent Ca(2+) influx independent of S1P receptors, whereas external application of S1P stimulated S1P receptor-dependent Ca(2+) 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 Ca(2+) influx and identify SOCs as a potential intracellular target for SK1.
authors: Department of Pathology (P.C.W.), Yale-New Haven Hospital, New Haven, Connecticut 06510; Departments of Medicine (W.R.F., S.M.G., A.A.J., L.M.L., H.M.E.) and Biochemistry and Molecular Biology (L.M.L.), Medical University of South Carolina, Charleston, South Carolina 29425; Department of Research Service (L.M.L.), Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401; Department of Physiology (M.W.B.), Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia 30912; and Department of Biochemistry and Molecular Genetics (A.A.J.), Faculty of Medicine, American University of Beirut, Beirut, Lebanon 113-6044.
authors: Parker C
authors: PC
authors: Wilson
authors: Department of Pathology (P.C.W.), Yale-New Haven Hospital, New Haven, Connecticut 06510; Departments of Medicine (W.R.F., S.M.G., A.A.J., L.M.L., H.M.E.) and Biochemistry and Molecular Biology (L.M.L.), Medical University of South Carolina, Charleston, South Carolina 29425; Department of Research Service (L.M.L.), Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401; Department of Physiology (M.W.B.), Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia 30912; and Department of Biochemistry and Molecular Genetics (A.A.J.), Faculty of Medicine, American University of Beirut, Beirut, Lebanon 113-6044.
authors: Wayne R
authors: WR
authors: Fitzgibbon
authors: Department of Pathology (P.C.W.), Yale-New Haven Hospital, New Haven, Connecticut 06510; Departments of Medicine (W.R.F., S.M.G., A.A.J., L.M.L., H.M.E.) and Biochemistry and Molecular Biology (L.M.L.), Medical University of South Carolina, Charleston, South Carolina 29425; Department of Research Service (L.M.L.), Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401; Department of Physiology (M.W.B.), Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia 30912; and Department of Biochemistry and Molecular Genetics (A.A.J.), Faculty of Medicine, American University of Beirut, Beirut, Lebanon 113-6044.
authors: Sara M
authors: SM
authors: Garrett
authors: Department of Pathology (P.C.W.), Yale-New Haven Hospital, New Haven, Connecticut 06510; Departments of Medicine (W.R.F., S.M.G., A.A.J., L.M.L., H.M.E.) and Biochemistry and Molecular Biology (L.M.L.), Medical University of South Carolina, Charleston, South Carolina 29425; Department of Research Service (L.M.L.), Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401; Department of Physiology (M.W.B.), Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia 30912; and Department of Biochemistry and Molecular Genetics (A.A.J.), Faculty of Medicine, American University of Beirut, Beirut, Lebanon 113-6044.
authors: Ayad A
authors: AA
authors: Jaffa
authors: Department of Pathology (P.C.W.), Yale-New Haven Hospital, New Haven, Connecticut 06510; Departments of Medicine (W.R.F., S.M.G., A.A.J., L.M.L., H.M.E.) and Biochemistry and Molecular Biology (L.M.L.), Medical University of South Carolina, Charleston, South Carolina 29425; Department of Research Service (L.M.L.), Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401; Department of Physiology (M.W.B.), Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia 30912; and Department of Biochemistry and Molecular Genetics (A.A.J.), Faculty of Medicine, American University of Beirut, Beirut, Lebanon 113-6044.
authors: Louis M
authors: LM
authors: Luttrell
authors: Department of Pathology (P.C.W.), Yale-New Haven Hospital, New Haven, Connecticut 06510; Departments of Medicine (W.R.F., S.M.G., A.A.J., L.M.L., H.M.E.) and Biochemistry and Molecular Biology (L.M.L.), Medical University of South Carolina, Charleston, South Carolina 29425; Department of Research Service (L.M.L.), Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401; Department of Physiology (M.W.B.), Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia 30912; and Department of Biochemistry and Molecular Genetics (A.A.J.), Faculty of Medicine, American University of Beirut, Beirut, Lebanon 113-6044.
authors: Michael W
authors: MW
authors: Brands
authors: Department of Pathology (P.C.W.), Yale-New Haven Hospital, New Haven, Connecticut 06510; Departments of Medicine (W.R.F., S.M.G., A.A.J., L.M.L., H.M.E.) and Biochemistry and Molecular Biology (L.M.L.), Medical University of South Carolina, Charleston, South Carolina 29425; Department of Research Service (L.M.L.), Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401; Department of Physiology (M.W.B.), Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia 30912; and Department of Biochemistry and Molecular Genetics (A.A.J.), Faculty of Medicine, American University of Beirut, Beirut, Lebanon 113-6044.
authors: Hesham M
authors: HM
authors: El-Shewy
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002908:Chronic Disease; D004789:Enzyme Activation / Q000187:drug effects; D017353:Gene Deletion; D057809:HEK293 Cells; D006801:Humans; D006973:Hypertension / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D008246:Lysophospholipids / Q000096:biosynthesis / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000494:pharmacology; D000099157:Sphingosine Kinase
chemical_list: D000804:Angiotensin II; D002118:Calcium; D015220:Calcium Channels; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate