CCR2+ Monocyte-Derived Infiltrating Macrophages Are Required for Adverse Cardiac Remodeling During Pressure Overload

[Display omitted] •Hypothesis: CCR2+ monocyte-derived cardiac macrophages are required for adverse LV remodeling, cardiac T-cell expansion, and the transition to HF following pressure overload.•The imposition of pressure overload via TAC resulted in the early up-regulation of CCL2, CCL7, and CCL12 c...

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Veröffentlicht in:	JACC. Basic to translational science Jg. 3; H. 2; S. 230 - 244
Hauptverfasser:	Patel, Bindiya, Bansal, Shyam S., Ismahil, Mohamed Ameen, Hamid, Tariq, Rokosh, Gregg, Mack, Matthias, Prabhu, Sumanth D.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States Elsevier Inc 01.04.2018 Elsevier
Schlagworte:	cardiac remodeling Cardiovascular heart failure inflammation macrophages PRECLINICAL RESEARCH T cells LN BNP LV T cells TNF IFN macrophages inflammation MerTK CCR2 PBS heart failure EF IL ICAM i.p EDTA CCL VCAM TGF APC cardiac remodeling TAC HF DC intraperitoneally ejection fraction phosphate-buffered saline c-mer proto-oncogene tyrosine kinase ethylenediaminetetraacetic acid C-C chemokine receptor 2 left ventricular interleukin C-C motif chemokine ligand interferon B-type natriuretic peptide tumor necrosis factor lymph node transverse aortic constriction antigen presenting cell vascular cell adhesion molecule transforming growth factor intercellular adhesion molecule dendritic cell BNP, B-type natriuretic peptide DC, dendritic cell EDTA, ethylenediaminetetraacetic acid PBS, phosphate-buffered saline TGF, transforming growth factor HF, heart failure APC, antigen presenting cell EF, ejection fraction ICAM, intercellular adhesion molecule CCR2, C-C chemokine receptor 2 LN, lymph node IFN, interferon TNF, tumor necrosis factor i.p., intraperitoneally TAC, transverse aortic constriction VCAM, vascular cell adhesion molecule LV, left ventricular IL, interleukin MerTK, c-mer proto-oncogene tyrosine kinase CCL, C-C motif chemokine ligand
ISSN:	2452-302X, 2452-302X
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Zusammenfassung:	[Display omitted] •Hypothesis: CCR2+ monocyte-derived cardiac macrophages are required for adverse LV remodeling, cardiac T-cell expansion, and the transition to HF following pressure overload.•The imposition of pressure overload via TAC resulted in the early up-regulation of CCL2, CCL7, and CCL12 chemokines in the LV, increased Ly6ChiCCR2+ monocytes in the blood, and augmented CCR2+ infiltrating macrophages in the heart.•Specific and circumscribed inhibition of CCR2+ monocytes and macrophages early during pressure overload reduced pathological hypertrophy, fibrosis, and systolic dysfunction during the late phase of pressure overload.•The early expansion of CCR2+ macrophages after pressure overload was required for long-term cardiac T-cell expansion.•CCR2+ monocytes/macrophages may represent key targets for immunomodulation to delay or prevent HF in pressure-overload states. Although chronic inflammation is a central feature of heart failure (HF), the immune cell profiles differ with different underlying causes. This suggests that for immunomodulatory therapy in HF to be successful, it needs to be tailored to the specific etiology. Here, the authors demonstrate that monocyte-derived C-C chemokine receptor 2 (CCR2)+ macrophages infiltrate the heart early during pressure overload in mice, and that blocking this response either pharmacologically or with antibody-mediated CCR2+ monocyte depletion alleviates late pathological left ventricular remodeling and dysfunction, T-cell expansion, and cardiac fibrosis. Hence, suppression of CCR2+ monocytes/macrophages may be an important immunomodulatory therapeutic target to ameliorate pressure-overload HF.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2452-302X 2452-302X
DOI:	10.1016/j.jacbts.2017.12.006