title: Sphingosine-1-phosphate and sphingosine kinase are critical for transforming growth factor-beta-stimulated collagen production by cardiac fibroblasts.
abstract: OBJECTIVE
  Following injury, fibroblasts transform into myofibroblasts and produce extracellular matrix (ECM). Excess production of ECM associated with cardiac fibrosis severely inhibits cardiac function. Sphingosine-1-phosphate (S1P), a bioactive lysophospholipid, regulates the function of numerous cell types. In this study, we determined the role of S1P in promoting pro-fibrotic actions of cardiac fibroblasts (CFs).
  
  
  RESULTS
  S1P-mediated effects on myofibroblast transformation, collagen production, and cross-talk with transforming growth factor-beta (TGF-beta) using mouse CF were examined. S1P increased alpha-smooth muscle actin (a myofibroblast marker) and collagen expression in a S1P2 receptor- and Rho kinase-dependent manner. TGF-beta increased sphingosine kinase 1 (SphK1; the enzyme responsible for S1P production) expression and activity. TGF-beta-stimulated collagen production was inhibited by SphK1 or S1P2 siRNA, a SphK inhibitor, and an anti-S1P monoclonal antibody.
  
  
  CONCLUSIONS
  These findings suggest that TGF-beta-stimulated collagen production in CF involves 'inside-out' S1P signalling whereby S1P produced intracellularly by SphK1 can be released and act in an autocrine/paracrine fashion to activate S1P2 and increase collagen production.
authors.affiliation: Department of Biology, San Diego State University, 5500 Campanile Dr, San Diego, CA 92182-4614, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Gellings Lowe
authors.forename: James S
authors.initials: JS
authors.lastname: Swaney
authors.forename: Kelli M
authors.initials: KM
authors.lastname: Moreno
authors.forename: Roger A
authors.initials: RA
authors.lastname: Sabbadini
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008233:Lymphotoxin-alpha / Q000494:pharmacology*; D008246:Lysophospholipids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D000911:Antibodies, Monoclonal; D003094:Collagen; D004791:Enzyme Inhibitors; D008233:Lymphotoxin-alpha; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D034741:RNA, Small Interfering; D013110:Sphingosine; D054460:rho-Associated Kinases; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate