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Proc Natl Acad Sci U S A. 2018 May 15;115(20):E4661-E4669. doi: 10.1073/pnas.1720065115. Epub 2018 Apr 30.

Distinct roles of resident and nonresident macrophages in nonischemic cardiomyopathy.

Author information

1
Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH 44106; xudong.liao@case.edu mukesh.jain2@case.edu.
2
Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106.
3
Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
4
Department of Cardiology, Tongji Hospital of Tongji University, 20065 Shanghai, China.
5
Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106.
6
National Center for Regenerative Medicine, Seidman Cancer Center, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH 44106.
7
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
8
Yale Cardiovascular Research Center, Yale University, New Haven, CT 06511.
9
Electron Microscopy Core Facility, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
10
Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
11
Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
12
Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106.

Abstract

Nonischemic cardiomyopathy (NICM) resulting from long-standing hypertension, valvular disease, and genetic mutations is a major cause of heart failure worldwide. Recent observations suggest that myeloid cells can impact cardiac function, but the role of tissue-intrinsic vs. tissue-extrinsic myeloid cells in NICM remains poorly understood. Here, we show that cardiac resident macrophage proliferation occurs within the first week following pressure overload hypertrophy (POH; a model of heart failure) and is requisite for the heart's adaptive response. Mechanistically, we identify Kruppel-like factor 4 (KLF4) as a key transcription factor that regulates cardiac resident macrophage proliferation and angiogenic activities. Finally, we show that blood-borne macrophages recruited in late-phase POH are detrimental, and that blockade of their infiltration improves myocardial angiogenesis and preserves cardiac function. These observations demonstrate previously unappreciated temporal and spatial roles for resident and nonresident macrophages in the development of heart failure.

KEYWORDS:

angiogenesis; cardiac macrophage; pressure overload hypertrophy

PMID:
29712858
PMCID:
PMC5960298
DOI:
10.1073/pnas.1720065115
[Indexed for MEDLINE]
Free PMC Article

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