Impaired Infarct Healing in Atherosclerotic Mice With Ly-6Chi Monocytosis

Peter Panizzi, Filip K. Swirski, Jose Luiz Figueiredo, Peter Waterman, David E. Sosnovik, Elena Aikawa, Peter Libby, Mikael Pittet, Ralph Weissleder, Matthias Nahrendorf

Research output: Contribution to journalArticlepeer-review

271 Scopus citations

Abstract

Objectives: 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-6Chi monocytes dominate on Day 1 to Day 4 and digest damaged tissue; reparative Ly-6Clo monocytes dominate on Day 5 to Day 10 and promote angiogenesis and scar formation. However, the monocyte repertoire is disturbed in atherosclerotic mice: Ly-6Chi 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 >10× more Ly-6Chi 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-6Chi 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-6Chi monocytosis. Conclusions: Ly-6Chi 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.

Original languageEnglish
Pages (from-to)1629-1638
Number of pages10
JournalJournal of the American College of Cardiology
Volume55
Issue number15
DOIs
StatePublished - 13 Apr 2010
Externally publishedYes

Keywords

  • FMT
  • healing
  • heart failure
  • monocytes
  • myocardial infarction

Fingerprint

Dive into the research topics of 'Impaired Infarct Healing in Atherosclerotic Mice With Ly-6Chi Monocytosis'. Together they form a unique fingerprint.

Cite this