title: Impaired infarct healing in atherosclerotic mice with Ly-6C(hi) monocytosis.
abstract: OBJECTIVE
  The aim of this study was to test whether blood monocytosis in mice with atherosclerosis affects infarct healing.
  
  
  BACKGROUND
  Monocytes are cellular protagonists of tissue repair, and their specific subtypes regulate the healing program after myocardial infarction (MI). Inflammatory Ly-6C(hi) monocytes dominate on Day 1 to Day 4 and digest damaged tissue; reparative Ly-6C(lo) monocytes dominate on Day 5 to Day 10 and promote angiogenesis and scar formation. However, the monocyte repertoire is disturbed in atherosclerotic mice: Ly-6C(hi) monocytes expand selectively, which might disrupt the resolution of inflammation.
  
  
  METHODS
  Ex vivo analysis of infarcts included flow cytometric monocyte enumeration, immunoactive staining, and quantitative polymerase chain reaction. To relate inflammatory activity to left ventricular remodeling, we used a combination of noninvasive fluorescence molecular tomography (FMT-CT) and physiologic imaging (magnetic resonance imaging).
  
  
  RESULTS
  Five-day-old infarcts showed >10x more Ly-6C(hi) monocytes in atherosclerotic (apoE(-/-)) mice compared with wild-type mice. The injured tissue in apoE(-/-) mice also showed a more pronounced inflammatory gene expression profile (e.g., increased tumor necrosis factor-alpha and myeloperoxidase and decreased transforming growth factor-beta) and a higher abundance of proteases, which are associated with the activity of Ly-6C(hi) monocytes. The FMT-CT on Day 5 after MI showed higher proteolysis and phagocytosis in infarcts of atherosclerotic mice. Serial magnetic resonance imaging showed accelerated deterioration of ejection fraction between Day 1 and Day 21 after MI in apoE(-/-). Finally, we could recapitulate these features in wild-type mice with artificially induced Ly-6C(hi) monocytosis.
  
  
  CONCLUSIONS
  Ly-6C(hi) monocytosis disturbs resolution of inflammation in murine infarcts and consequently enhances left ventricular remodeling. These findings position monocyte subsets as potential therapeutic targets to augment tissue repair after infarction and to prevent post-MI heart failure.
authors.affiliation: Center for Systems Biology, Simches Research Building, Massachusetts General Hospital and Harvard Medical School Boston, Massachusetts 02114, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Panizzi
authors.forename: Filip K
authors.initials: FK
authors.lastname: Swirski
authors.forename: Jose-Luiz
authors.initials: JL
authors.lastname: Figueiredo
authors.forename: Peter
authors.initials: P
authors.lastname: Waterman
authors.forename: David E
authors.initials: DE
authors.lastname: Sosnovik
authors.forename: Elena
authors.initials: E
authors.lastname: Aikawa
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Mikael
authors.initials: M
authors.lastname: Pittet
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis* / Q000235:genetics; D050197:Atherosclerosis / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D007958:Leukocyte Count; D007964:Leukocytosis / Q000378:metabolism* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D009203:Myocardial Infarction / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012038:Regeneration; D014057:Tomography, X-Ray Computed; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D000950:Antigens, Ly; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D004247:DNA