title: FoxO4 promotes early inflammatory response upon myocardial infarction via endothelial Arg1.
abstract: BACKGROUND
  Inflammation in post-myocardial infarction (MI) is necessary for myocyte repair and wound healing. Unfortunately, it is also a key component of subsequent heart failure pathology. Transcription factor forkhead box O4 (FoxO4) regulates a variety of biological processes, including inflammation. However, its role in MI remains unknown.
  
  
  OBJECTIVE
  To test the hypothesis that FoxO4 promotes early post-MI inflammation via endothelial arginase 1 (Arg1).
  
  
  RESULTS
  We induced MI in wild-type and FoxO4(-/-) mice. FoxO4(-/-) mice had a significantly higher post-MI survival, better cardiac function, and reduced infarct size. FoxO4(-/-) hearts had significantly fewer neutrophils, reduced expression of cytokines, and competitive nitric oxide synthase inhibitor Arg1. We generated conditional FoxO4 knockout mice with FoxO4 deleted in cardiac mycoytes or endothelial cells. FoxO4 endothelial cell-specific knockout mice showed significant post-MI improvement of cardiac function and reduction of neutrophil accumulation and cytokine expression, whereas FoxO4 cardiac mycoyte-specific knockout mice had no significant difference in cardiac function and post-MI inflammation from those of control littermates. FoxO4 binds the Foxo-binding site in the Arg1 promoter and activates Arg1 transcription. FoxO4 knockdown in human aortic endothelial cells upregulated nitric oxide on ischemia and suppressed monocyte adhesion that can be reversed by ectopic-expression of Arg1. Furthermore, chemical inhibition of Arg1 in wild-type mice had similar cardioprotection and reduced inflammation after MI as FoxO4 inactivation and administration of nitric oxide synthase inhibitor to FoxO4 KO mice reversed the beneficial effects of FoxO4 deletion on post-MI cardiac function.
  
  
  CONCLUSIONS
  FoxO4 activates Arg1 transcription in endothelial cells in response to MI, leading to downregulation of nitric oxide and upregulation of neutrophil infiltration to the infarct area.
authors.affiliation: From the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA (S.M.M.).
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.affiliation: From the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA (S.M.M.).
authors.forename: Sean C
authors.initials: SC
authors.lastname: Goetsch
authors.affiliation: From the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA (S.M.M.).
authors.forename: Zhaoning
authors.initials: Z
authors.lastname: Wang
authors.affiliation: From the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA (S.M.M.).
authors.forename: Robert
authors.initials: R
authors.lastname: Luo
authors.affiliation: From the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA (S.M.M.).
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
authors.affiliation: From the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA (S.M.M.).
authors.forename: Jay
authors.initials: J
authors.lastname: Schneider
authors.affiliation: From the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA (S.M.M.).
authors.forename: Sidney M
authors.initials: SM
authors.lastname: Morris
authors.affiliation: From the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA (S.M.M.). zhi-ping.Liu@utsouthwestern.edu.
authors.forename: Zhi-Ping
authors.initials: ZP
authors.lastname: Liu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001119:Arginase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D001665:Binding Sites; D002448:Cell Adhesion; D018797:Cell Cycle Proteins; D018920:Coculture Techniques; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D004790:Enzyme Induction; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D020556:Neutrophil Infiltration; D009569:Nitric Oxide / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D020298:U937 Cells
chemical_list: D000893:Anti-Inflammatory Agents; D018797:Cell Cycle Proteins; C108803:FOXO4 protein, human; D051858:Forkhead Transcription Factors; C525394:FoxO4 protein, mouse; D014157:Transcription Factors; D009569:Nitric Oxide; C574619:ARG1 protein, human; C544448:Arg1 protein, mouse; D001119:Arginase
keywords: FoxO4 protein, mouse; arginase; endothelial cells; inflammation; myocardial infarction