Proliferation and Recruitment Contribute to Myocardial Macrophage Expansion in Chronic Heart Failure
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nihms852481.pdf
Description
Accepted version
Size
2.73 MB
Format
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Checksum (MD5)
03f65088a0552d165ff77f1932c72628
Author(s)
Sager, Hendrik B.
Hulsmans, Maarten
Lavine, Kory J.
Moreira, Marina B.
Heidt, Timo
Courties, Gabriel
Sun, Yuan
Iwamoto, Yoshiko
Tricot, Benoit
Khan, Omar Fizal
Date Issued
September 2016
Journal
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Citation
Sager, Hendrik et al. "Proliferation and Recruitment Contribute to Myocardial Macrophage Expansion in Chronic Heart Failure." Circulation Research 119, 7 (July 2016): 853-864 © 2016 American Heart Association, Inc
Version
Author's final manuscript
Abstract
Rationale: Macrophages reside in the healthy myocardium, participate in ischemic heart disease, and modulate myocardial infarction (MI) healing. Their origin and roles in post-MI remodeling of nonischemic remote myocardium, however, remain unclear. Objective: This study investigated the number, origin, phenotype, and function of remote cardiac macrophages residing in the nonischemic myocardium in mice with chronic heart failure after coronary ligation. Methods and Results: Eight weeks post MI, fate mapping and flow cytometry revealed that a 2.9-fold increase in remote macrophages results from both increased local macrophage proliferation and monocyte recruitment. Heart failure produced by extensive MI, through activation of the sympathetic nervous system, expanded medullary and extramedullary hematopoiesis. Circulating Ly6C high monocytes rose from 64±5 to 108±9 per microliter of blood (P<0.05). Cardiac monocyte recruitment declined in Ccr2 -/- mice, reducing macrophage numbers in the failing myocardium. Mechanical strain of primary murine and human macrophage cultures promoted cell cycle entry, suggesting that the increased wall tension in post-MI heart failure stimulates local macrophage proliferation. Strained cells activated the mitogen-activated protein kinase pathway, whereas specific inhibitors of this pathway reduced macrophage proliferation in strained cell cultures and in the failing myocardium (P<0.05). Steady-state cardiac macrophages, monocyte-derived macrophages, and locally sourced macrophages isolated from failing myocardium expressed different genes in a pattern distinct from the M1/M2 macrophage polarization paradigm. In vivo silencing of endothelial cell adhesion molecules curbed post-MI monocyte recruitment to the remote myocardium and preserved ejection fraction (27.4±2.4 versus 19.1±2%; P<0.05). Conclusions: Myocardial failure is influenced by an altered myeloid cell repertoire. Keywords: myocardial infarction; hypertropy; heart failure; macrophage; monocyte
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1161/circresaha.116.309001
