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Impaired Infarct Healing in Atherosclerotic Mice With Ly-6ChiMonocytosis

2010; Elsevier BV; Volume: 55; Issue: 15 Linguagem: Inglês

10.1016/j.jacc.2009.08.089

1558-3597

Peter Panizzi, Filip K. Świrski, Jose‐Luiz Figueiredo, Peter Waterman, David E. Sosnovik, Elena Aïkawa, Peter Libby, Mikaël J. Pittet, Ralph Weissleder, Matthias Nahrendorf,

Immune cells in cancer

The aim of this study was to test whether blood monocytosis in mice with atherosclerosis affects infarct healing. Monocytes are cellular protagonists of tissue repair, and their specific subtypes regulate the healing program after myocardial infarction (MI). Inflammatory Ly-6Chimonocytes dominate on Day 1 to Day 4 and digest damaged tissue; reparative Ly-6Clomonocytes dominate on Day 5 to Day 10 and promote angiogenesis and scar formation. However, the monocyte repertoire is disturbed in atherosclerotic mice: Ly-6Chimonocytes expand selectively, which might disrupt the resolution of inflammation. 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). Five-day-old infarcts showed >10× more Ly-6Chimonocytes 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-6Chimonocytes. 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-6Chimonocytosis. Ly-6Chimonocytosis 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.