Proliferation and Recruitment Contribute to Myocardial Macrophage Expansion in Chronic Heart Failure
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 non-ischemic remote myocardium, however, remain unclear.
Objective: This study investigated the number, origin, phenotype and function of remote cardiac macrophages residing in the non-ischemic 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 Ly6Chigh monocytes rose from 64±5 to 108±9 /µl 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 MAPK pathway, while 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 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 vs.19.1±2%, p<0.05).
Conclusions: Myocardial failure is influenced by an altered myeloid cell repertoire.
- Received April 28, 2016.
- Revision received July 18, 2016.
- Accepted July 21, 2016.