Kristine Y DeLeon-Pennell1, Yuan Tian2, Bai Zhang2, Courtney A Cates2, Rugmani Padmanabhan Iyer2, Presley Cannon2, Punit Shah2, Paul Aiyetan2, Ganesh V Halade2, Yonggang Ma2, Elizabeth Flynn2, Zhen Zhang2, Yu-Fang Jin2, Hui Zhang2, Merry L Lindsey1. 1. 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. 2. 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.).
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. METHODS AND 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.
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. METHODS AND 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.
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