title: Insulin-like growth factor I reduces lipid oxidation and foam cell formation via downregulation of 12/15-lipoxygenase.
abstract: OBJECTIVE
  We have shown that insulin-like growth factor I (IGF-1) infusion in Apoe(-/-) mice decreased atherosclerotic plaque size and plaque macrophage and lipid content suggesting that IGF-1 suppressed formation of macrophage-derived foam cells. Since 12/15-lipoxygenase (12/15-LOX) plays an important role in OxLDL and foam cell formation, we hypothesized that IGF-1 downregulates 12/15-LOX, thereby suppressing lipid oxidation and foam cell formation.
  
  
  RESULTS
  We found that IGF-1 decreased 12/15-LOX plaque immunopositivity and serum OxLDL levels in Apoe(-/-) mice. IGF-1 reduced 12/15-LOX protein and mRNA levels in cultured THP-1 macrophages and IGF-1 also decreased expression of STAT6 transcription factor. IGF-1 reduction in macrophage 12/15-LOX was mediated in part via a PI3 kinase- and STAT6-dependent transcriptional mechanism. IGF-1 suppressed THP-1 macrophage ability to oxidize lipids and form foam cells. IGF-1 downregulated 12/15-LOX in human blood-derived primary macrophages and IGF-1 decreased LDL oxidation induced by these cells. IGF-1 reduced LDL oxidation and formation of foam cells by wild type murine peritoneal macrophages, however these effects were completely blocked in 12/15-LOX-null macrophages suggesting that the ability of IGF-1 to reduce LDL oxidation and foam cells formation is dependent on its ability to downregulate 12/15-LOX.
  
  
  CONCLUSIONS
  Overall our data demonstrate that IGF-1 reduces lipid oxidation and foam cell formation via downregulation of 12/15-LOX and this mechanism may play a major role in the anti-atherosclerotic effects of IGF-1.
authors.affiliation: Heart and Vascular Institute, School of Medicine, Tulane University, New Orleans, LA 70112, USA. Electronic address: ssukhano@tulane.edu.
authors.forename: Sergiy
authors.initials: S
authors.lastname: Sukhanov
authors.affiliation: Heart and Vascular Institute, School of Medicine, Tulane University, New Orleans, LA 70112, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Snarski
authors.affiliation: Heart and Vascular Institute, School of Medicine, Tulane University, New Orleans, LA 70112, USA.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Vaughn
authors.affiliation: Heart and Vascular Institute, School of Medicine, Tulane University, New Orleans, LA 70112, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Lobelle-Rich
authors.affiliation: Heart and Vascular Institute, School of Medicine, Tulane University, New Orleans, LA 70112, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Kim
authors.affiliation: Heart and Vascular Institute, School of Medicine, Tulane University, New Orleans, LA 70112, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Higashi
authors.affiliation: Heart and Vascular Institute, School of Medicine, Tulane University, New Orleans, LA 70112, USA.
authors.forename: Shaw-Yung
authors.initials: SY
authors.lastname: Shai
authors.affiliation: Heart and Vascular Institute, School of Medicine, Tulane University, New Orleans, LA 70112, USA.
authors.forename: Patrice
authors.initials: P
authors.lastname: Delafontaine
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005487:Foam Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage*; D008077:Lipoproteins, LDL / Q000097:blood / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C475064:12-15-lipoxygenase; D001057:Apolipoproteins E; C583557:IGF1 protein, human; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C099252:oxidized low density lipoprotein; D007334:Insulin-Like Growth Factor I; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D058539:Phosphatidylinositol 3-Kinase
keywords: Atherosclerosis; Foam cells; LDL/Oxidation/antioxidants; Lipoxygenase; Macrophages/monocytes; Oxidized lipids