title: Effect of the sphingosine kinase 1 selective inhibitor, PF-543 on arterial and cardiac remodelling in a hypoxic model of pulmonary arterial hypertension.
abstract: Recent studies have demonstrated that the expression of sphingosine kinase 1, the enzyme that catalyses formation of the bioactive lipid, sphingosine 1-phosphate, is increased in lungs from patients with pulmonary arterial hypertension. In addition, Sk1(-/-) mice are protected from hypoxic-induced pulmonary arterial hypertension. Therefore, we assessed the effect of the sphingosine kinase 1 selective inhibitor, PF-543 and a sphingosine kinase 1/ceramide synthase inhibitor, RB-005 on pulmonary and cardiac remodelling in a mouse hypoxic model of pulmonary arterial hypertension. Administration of the potent sphingosine kinase 1 inhibitor, PF-543 in a mouse hypoxic model of pulmonary hypertension had no effect on vascular remodelling but reduced right ventricular hypertrophy. The latter was associated with a significant reduction in cardiomyocyte death. The protection involves a reduction in the expression of p53 (that promotes cardiomyocyte death) and an increase in the expression of anti-oxidant nuclear factor (erythroid-derived 2)-like 2 (Nrf-2). In contrast, RB-005 lacked effects on right ventricular hypertrophy, suggesting that sphingosine kinase 1 inhibition might be nullified by concurrent inhibition of ceramide synthase. Therefore, our findings with PF-543 suggest an important role for sphingosine kinase 1 in the development of hypertrophy in pulmonary arterial hypertension.
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow G4 0RE, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: MacRitchie
authors.affiliation: Department of Biological Chemistry, Weizmann Insitute of Science, Rehovot 76100, Israel.
authors.forename: Giora
authors.initials: G
authors.lastname: Volpert
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow G4 0RE, UK.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al Washih
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow G4 0RE, UK.
authors.forename: David G
authors.initials: DG
authors.lastname: Watson
authors.affiliation: Department of Biological Chemistry, Weizmann Insitute of Science, Rehovot 76100, Israel.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, G12 8QQ, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Kennedy
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow G4 0RE, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Pyne
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow G4 0RE, UK. Electronic address: n.j.pyne@strath.ac.uk.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Pyne
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D057809:HEK293 Cells; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000503:physiopathology*; D017380:Hypertrophy, Right Ventricular / Q000473:pathology / Q000503:physiopathology; D000860:Hypoxia / Q000097:blood / Q000503:physiopathology*; D000432:Methanol; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010880:Piperidines / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D011312:Pressure; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D011759:Pyrrolidines / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013450:Sulfones / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D020257:Ventricular Remodeling / Q000187:drug effects*; D000099157:Sphingosine Kinase
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D000432:Methanol; D017853:Phosphotransferases (Alcohol Group Acceptor); D010880:Piperidines; D011759:Pyrrolidines; D013450:Sulfones; D000099157:Sphingosine Kinase; C583391:1-(4-octylphenethyl)piperidin-4-ol; C573330:PF-543
keywords: Hypertrophy; Hypoxia; Pulmonary arterial hypertension; Sphingosine 1-phosphate; Sphingosine kinase; Vascular remodelling