title: Lp-PLA2 Antagonizes Left Ventricular Healing After Myocardial Infarction by Impairing the Appearance of Reparative Macrophages.
abstract: BACKGROUND
  Healing after myocardial infarction (MI) involves the biphasic accumulation of inflammatory Ly-6C(high) and reparative Ly-6C(low) monocytes/macrophages. Excessive inflammation disrupts the balance between the 2 phases, impairs infarct healing, and contributes to left ventricle remodeling and heart failure. Lipoprotein-associated phospholipase A2 (Lp-PLA2), a member of the phospholipase A2 family of enzymes, produced predominantly by leukocytes, participates in host defenses and disease. Elevated Lp-PLA2 levels associate with increased risk of cardiovascular events across diverse patient populations, but the mechanisms by which the enzyme elicits its effects remain unclear. This study tested the role of Lp-PLA2 in healing after MI.
  
  
  RESULTS
  In response to MI, Lp-PLA2 levels markedly increased in the circulation. To test the functional importance of Lp-PLA2, we generated chimeric mice whose bone marrow-derived leukocytes were Lp-PLA2-deficient (bmLp-PLA2 (-/-)). Compared with wild-type controls, bmLp-PLA2 (-/-) mice subjected to MI had lower serum levels of inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, and decreased number of circulating inflammatory myeloid cells. Accordingly, bmLp-PLA2 (-/-) mice developed smaller and less inflamed infarcts with reduced numbers of infiltrating neutrophils and inflammatory Ly-6C(high) monocytes. During the later, reparative phase, infarcts of bmLp-PLA2 (-/-) mice contained Ly-6C(low) macrophages with a skewed M2-prone gene expression signature, increased collagen deposition, fewer inflammatory cells, and improved indices of angiogenesis. Consequently, the hearts of bmLp-PLA2 (-/-) mice healed more efficiently, as determined by improved left ventricle remodeling and ejection fraction.
  
  
  CONCLUSIONS
  Lp-PLA2 augments the inflammatory response after MI and antagonizes healing by disrupting the balance between inflammation and repair, providing a rationale for focused study of ventricular function and heart failure after targeting this enzyme acutely in MI.
authors.affiliation: From the Center for Systems Biology, Massachusetts General Hospital, Boston (S.H., B.G.C., A.F., A.A., M.N., I.H., Y.S., Y.-X.Y., Y.I., B.T., R.W., M.N., F.K.S.); Biological Sciences, GlaxoSmithKline, Collegeville, PA (M.B.); Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.); GlaxoSmithKline, King of Prussia, PA (C.M.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.L.).
authors.forename: Shun
authors.initials: S
authors.lastname: He
authors.affiliation: From the Center for Systems Biology, Massachusetts General Hospital, Boston (S.H., B.G.C., A.F., A.A., M.N., I.H., Y.S., Y.-X.Y., Y.I., B.T., R.W., M.N., F.K.S.); Biological Sciences, GlaxoSmithKline, Collegeville, PA (M.B.); Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.); GlaxoSmithKline, King of Prussia, PA (C.M.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.L.).
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Chousterman
authors.affiliation: From the Center for Systems Biology, Massachusetts General Hospital, Boston (S.H., B.G.C., A.F., A.A., M.N., I.H., Y.S., Y.-X.Y., Y.I., B.T., R.W., M.N., F.K.S.); Biological Sciences, GlaxoSmithKline, Collegeville, PA (M.B.); Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.); GlaxoSmithKline, King of Prussia, PA (C.M.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.L.).
authors.forename: Ashley
authors.initials: A
authors.lastname: Fenn
authors.affiliation: From the Center for Systems Biology, Massachusetts General Hospital, Boston (S.H., B.G.C., A.F., A.A., M.N., I.H., Y.S., Y.-X.Y., Y.I., B.T., R.W., M.N., F.K.S.); Biological Sciences, GlaxoSmithKline, Collegeville, PA (M.B.); Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.); GlaxoSmithKline, King of Prussia, PA (C.M.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.L.).
authors.forename: Atsushi
authors.initials: A
authors.lastname: Anzai
authors.affiliation: From the Center for Systems Biology, Massachusetts General Hospital, Boston (S.H., B.G.C., A.F., A.A., M.N., I.H., Y.S., Y.-X.Y., Y.I., B.T., R.W., M.N., F.K.S.); Biological Sciences, GlaxoSmithKline, Collegeville, PA (M.B.); Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.); GlaxoSmithKline, King of Prussia, PA (C.M.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.L.).
authors.forename: Manfred
authors.initials: M
authors.lastname: Nairz
authors.affiliation: From the Center for Systems Biology, Massachusetts General Hospital, Boston (S.H., B.G.C., A.F., A.A., M.N., I.H., Y.S., Y.-X.Y., Y.I., B.T., R.W., M.N., F.K.S.); Biological Sciences, GlaxoSmithKline, Collegeville, PA (M.B.); Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.); GlaxoSmithKline, King of Prussia, PA (C.M.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.L.).
authors.forename: Martin
authors.initials: M
authors.lastname: Brandt
authors.affiliation: From the Center for Systems Biology, Massachusetts General Hospital, Boston (S.H., B.G.C., A.F., A.A., M.N., I.H., Y.S., Y.-X.Y., Y.I., B.T., R.W., M.N., F.K.S.); Biological Sciences, GlaxoSmithKline, Collegeville, PA (M.B.); Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.); GlaxoSmithKline, King of Prussia, PA (C.M.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.L.).
authors.forename: Ingo
authors.initials: I
authors.lastname: Hilgendorf
authors.affiliation: From the Center for Systems Biology, Massachusetts General Hospital, Boston (S.H., B.G.C., A.F., A.A., M.N., I.H., Y.S., Y.-X.Y., Y.I., B.T., R.W., M.N., F.K.S.); Biological Sciences, GlaxoSmithKline, Collegeville, PA (M.B.); Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.); GlaxoSmithKline, King of Prussia, PA (C.M.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.L.).
authors.forename: Yuan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: From the Center for Systems Biology, Massachusetts General Hospital, Boston (S.H., B.G.C., A.F., A.A., M.N., I.H., Y.S., Y.-X.Y., Y.I., B.T., R.W., M.N., F.K.S.); Biological Sciences, GlaxoSmithKline, Collegeville, PA (M.B.); Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.); GlaxoSmithKline, King of Prussia, PA (C.M.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.L.).
authors.forename: Yu-Xiang
authors.initials: YX
authors.lastname: Ye
authors.affiliation: From the Center for Systems Biology, Massachusetts General Hospital, Boston (S.H., B.G.C., A.F., A.A., M.N., I.H., Y.S., Y.-X.Y., Y.I., B.T., R.W., M.N., F.K.S.); Biological Sciences, GlaxoSmithKline, Collegeville, PA (M.B.); Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.); GlaxoSmithKline, King of Prussia, PA (C.M.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.L.).
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwamoto
authors.affiliation: From the Center for Systems Biology, Massachusetts General Hospital, Boston (S.H., B.G.C., A.F., A.A., M.N., I.H., Y.S., Y.-X.Y., Y.I., B.T., R.W., M.N., F.K.S.); Biological Sciences, GlaxoSmithKline, Collegeville, PA (M.B.); Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.); GlaxoSmithKline, King of Prussia, PA (C.M.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.L.).
authors.forename: Benoit
authors.initials: B
authors.lastname: Tricot
authors.affiliation: From the Center for Systems Biology, Massachusetts General Hospital, Boston (S.H., B.G.C., A.F., A.A., M.N., I.H., Y.S., Y.-X.Y., Y.I., B.T., R.W., M.N., F.K.S.); Biological Sciences, GlaxoSmithKline, Collegeville, PA (M.B.); Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.); GlaxoSmithKline, King of Prussia, PA (C.M.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.L.).
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.affiliation: From the Center for Systems Biology, Massachusetts General Hospital, Boston (S.H., B.G.C., A.F., A.A., M.N., I.H., Y.S., Y.-X.Y., Y.I., B.T., R.W., M.N., F.K.S.); Biological Sciences, GlaxoSmithKline, Collegeville, PA (M.B.); Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.); GlaxoSmithKline, King of Prussia, PA (C.M.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.L.).
authors.forename: Colin
authors.initials: C
authors.lastname: Macphee
authors.affiliation: From the Center for Systems Biology, Massachusetts General Hospital, Boston (S.H., B.G.C., A.F., A.A., M.N., I.H., Y.S., Y.-X.Y., Y.I., B.T., R.W., M.N., F.K.S.); Biological Sciences, GlaxoSmithKline, Collegeville, PA (M.B.); Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.); GlaxoSmithKline, King of Prussia, PA (C.M.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.L.).
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.affiliation: From the Center for Systems Biology, Massachusetts General Hospital, Boston (S.H., B.G.C., A.F., A.A., M.N., I.H., Y.S., Y.-X.Y., Y.I., B.T., R.W., M.N., F.K.S.); Biological Sciences, GlaxoSmithKline, Collegeville, PA (M.B.); Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.); GlaxoSmithKline, King of Prussia, PA (C.M.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.L.).
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
authors.affiliation: From the Center for Systems Biology, Massachusetts General Hospital, Boston (S.H., B.G.C., A.F., A.A., M.N., I.H., Y.S., Y.-X.Y., Y.I., B.T., R.W., M.N., F.K.S.); Biological Sciences, GlaxoSmithKline, Collegeville, PA (M.B.); Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.); GlaxoSmithKline, King of Prussia, PA (C.M.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.L.). fswirski@mgh.harvard.edu.
authors.forename: Filip K
authors.initials: FK
authors.lastname: Swirski
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D019028:Magnetic Resonance Imaging, Cine; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D012313:RNA / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020257:Ventricular Remodeling / Q000235:genetics*; D014945:Wound Healing
chemical_list: D012313:RNA; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase
keywords: heart failure; inflammation; macrophages; monocytes; myocardial infarction