title: CD36 Is a Matrix Metalloproteinase-9 Substrate That Stimulates Neutrophil Apoptosis and Removal During Cardiac Remodeling.
abstract: BACKGROUND
  After myocardial infarction, the left ventricle undergoes a wound healing response that includes the robust infiltration of neutrophils and macrophages to facilitate removal of dead myocytes as well as turnover of the extracellular matrix. Matrix metalloproteinase (MMP)-9 is a key enzyme that regulates post-myocardial infarction left ventricular remodeling.
  
  
  RESULTS
  Infarct regions from wild-type and MMP-9 null mice (n=8 per group) analyzed by glycoproteomics showed that of 541 N-glycosylated proteins quantified, 45 proteins were at least 2-fold upregulated or downregulated with MMP-9 deletion (all P<0.05). Cartilage intermediate layer protein and platelet glycoprotein 4 (CD36) were identified as having the highest fold increase in MMP-9 null mice. By immunoblotting, CD36 but not cartilage intermediate layer protein decreased steadily during the time course post-myocardial infarction, which identified CD36 as a candidate MMP-9 substrate. MMP-9 was confirmed in vitro and in vivo to proteolytically degrade CD36. In vitro stimulation of day 7 post-myocardial infarction macrophages with MMP-9 or a CD36-blocking peptide reduced phagocytic capacity. Dual immunofluorescence revealed concomitant accumulation of apoptotic neutrophils in the MMP-9 null group compared with wild-type group. In vitro stimulation of isolated neutrophils with MMP-9 decreased neutrophil apoptosis, indicated by reduced caspase-9 expression.
  
  
  CONCLUSIONS
  Our data reveal a new cell-signaling role for MMP-9 through CD36 degradation to regulate macrophage phagocytosis and neutrophil apoptosis.
authors.affiliation: From the Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., M.L.L.); San Antonio Cardiovascular Proteomics Center, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., Y.-F.J., M.L.L.); Department of Electrical and Computer Engineering (Y.-F.J.), The University of Texas at San Antonio, San Antonio; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD (B.Z., P.S., P.A., Z.Z., H.Z.); Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham (G.V.H.); and Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS (M.L.L.). kdeleon@umc.edu mllindsey@umc.edu.
authors.forename: Kristine Y
authors.initials: KY
authors.lastname: DeLeon-Pennell
authors.affiliation: From the Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., M.L.L.); San Antonio Cardiovascular Proteomics Center, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., Y.-F.J., M.L.L.); Department of Electrical and Computer Engineering (Y.-F.J.), The University of Texas at San Antonio, San Antonio; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD (B.Z., P.S., P.A., Z.Z., H.Z.); Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham (G.V.H.); and Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS (M.L.L.).
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.affiliation: From the Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., M.L.L.); San Antonio Cardiovascular Proteomics Center, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., Y.-F.J., M.L.L.); Department of Electrical and Computer Engineering (Y.-F.J.), The University of Texas at San Antonio, San Antonio; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD (B.Z., P.S., P.A., Z.Z., H.Z.); Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham (G.V.H.); and Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS (M.L.L.).
authors.forename: Bai
authors.initials: B
authors.lastname: Zhang
authors.affiliation: From the Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., M.L.L.); San Antonio Cardiovascular Proteomics Center, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., Y.-F.J., M.L.L.); Department of Electrical and Computer Engineering (Y.-F.J.), The University of Texas at San Antonio, San Antonio; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD (B.Z., P.S., P.A., Z.Z., H.Z.); Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham (G.V.H.); and Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS (M.L.L.).
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Cates
authors.affiliation: From the Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., M.L.L.); San Antonio Cardiovascular Proteomics Center, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., Y.-F.J., M.L.L.); Department of Electrical and Computer Engineering (Y.-F.J.), The University of Texas at San Antonio, San Antonio; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD (B.Z., P.S., P.A., Z.Z., H.Z.); Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham (G.V.H.); and Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS (M.L.L.).
authors.forename: Rugmani Padmanabhan
authors.initials: RP
authors.lastname: Iyer
authors.affiliation: From the Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., M.L.L.); San Antonio Cardiovascular Proteomics Center, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., Y.-F.J., M.L.L.); Department of Electrical and Computer Engineering (Y.-F.J.), The University of Texas at San Antonio, San Antonio; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD (B.Z., P.S., P.A., Z.Z., H.Z.); Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham (G.V.H.); and Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS (M.L.L.).
authors.forename: Presley
authors.initials: P
authors.lastname: Cannon
authors.affiliation: From the Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., M.L.L.); San Antonio Cardiovascular Proteomics Center, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., Y.-F.J., M.L.L.); Department of Electrical and Computer Engineering (Y.-F.J.), The University of Texas at San Antonio, San Antonio; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD (B.Z., P.S., P.A., Z.Z., H.Z.); Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham (G.V.H.); and Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS (M.L.L.).
authors.forename: Punit
authors.initials: P
authors.lastname: Shah
authors.affiliation: From the Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., M.L.L.); San Antonio Cardiovascular Proteomics Center, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., Y.-F.J., M.L.L.); Department of Electrical and Computer Engineering (Y.-F.J.), The University of Texas at San Antonio, San Antonio; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD (B.Z., P.S., P.A., Z.Z., H.Z.); Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham (G.V.H.); and Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS (M.L.L.).
authors.forename: Paul
authors.initials: P
authors.lastname: Aiyetan
authors.affiliation: From the Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., M.L.L.); San Antonio Cardiovascular Proteomics Center, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., Y.-F.J., M.L.L.); Department of Electrical and Computer Engineering (Y.-F.J.), The University of Texas at San Antonio, San Antonio; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD (B.Z., P.S., P.A., Z.Z., H.Z.); Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham (G.V.H.); and Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS (M.L.L.).
authors.forename: Ganesh V
authors.initials: GV
authors.lastname: Halade
authors.affiliation: From the Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., M.L.L.); San Antonio Cardiovascular Proteomics Center, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., Y.-F.J., M.L.L.); Department of Electrical and Computer Engineering (Y.-F.J.), The University of Texas at San Antonio, San Antonio; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD (B.Z., P.S., P.A., Z.Z., H.Z.); Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham (G.V.H.); and Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS (M.L.L.).
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: From the Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., M.L.L.); San Antonio Cardiovascular Proteomics Center, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., Y.-F.J., M.L.L.); Department of Electrical and Computer Engineering (Y.-F.J.), The University of Texas at San Antonio, San Antonio; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD (B.Z., P.S., P.A., Z.Z., H.Z.); Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham (G.V.H.); and Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS (M.L.L.).
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Flynn
authors.affiliation: From the Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., M.L.L.); San Antonio Cardiovascular Proteomics Center, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., Y.-F.J., M.L.L.); Department of Electrical and Computer Engineering (Y.-F.J.), The University of Texas at San Antonio, San Antonio; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD (B.Z., P.S., P.A., Z.Z., H.Z.); Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham (G.V.H.); and Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS (M.L.L.).
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: From the Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., M.L.L.); San Antonio Cardiovascular Proteomics Center, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., Y.-F.J., M.L.L.); Department of Electrical and Computer Engineering (Y.-F.J.), The University of Texas at San Antonio, San Antonio; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD (B.Z., P.S., P.A., Z.Z., H.Z.); Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham (G.V.H.); and Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS (M.L.L.).
authors.forename: Yu-Fang
authors.initials: YF
authors.lastname: Jin
authors.affiliation: From the Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., M.L.L.); San Antonio Cardiovascular Proteomics Center, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., Y.-F.J., M.L.L.); Department of Electrical and Computer Engineering (Y.-F.J.), The University of Texas at San Antonio, San Antonio; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD (B.Z., P.S., P.A., Z.Z., H.Z.); Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham (G.V.H.); and Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS (M.L.L.).
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: From the Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., M.L.L.); San Antonio Cardiovascular Proteomics Center, University of Mississippi Medical Center, Jackson (K.Y.D.-P., Y.T., C.A.C., R.P.I., P.C., Y.M., E.F., Y.-F.J., M.L.L.); Department of Electrical and Computer Engineering (Y.-F.J.), The University of Texas at San Antonio, San Antonio; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD (B.Z., P.S., P.A., Z.Z., H.Z.); Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham (G.V.H.); and Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS (M.L.L.). kdeleon@umc.edu mllindsey@umc.edu.
authors.forename: Merry L
authors.initials: ML
authors.lastname: Lindsey
mesh_terms: D000818:Animals; D017209:Apoptosis; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism*; D059748:Proteolysis; D015398:Signal Transduction
chemical_list: D018955:CD36 Antigens; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: extracellular matrix; immunoblotting; infarction; inflammation; myocardial; proteomics