Self-Maintenance of Cardiac Resident Reparative Macrophages Attenuates Doxorubicin-Induced Cardiomyopathy Through the SR-A1-c-Myc Axis

Circ Res. 2020 Aug 14;127(5):610-627. doi: 10.1161/CIRCRESAHA.119.316428. Epub 2020 May 29.

Abstract

Rationale: Doxorubicin-induced cardiomyopathy (DiCM) is a primary cause of heart failure and mortality in cancer patients, in which macrophage-orchestrated inflammation serves as an essential pathological mechanism. However, the specific roles of tissue-resident and monocyte-derived macrophages in DiCM remain poorly understood.

Objective: Uncovering the origins, phenotypes, and functions of proliferative cardiac resident macrophages and mechanistic insights into the self-maintenance of cardiac macrophage during DiCM progression.

Methods and results: Mice were administrated with doxorubicin to induce cardiomyopathy. Dynamic changes of resident and monocyte-derived macrophages were examined by lineage tracing, parabiosis, and bone marrow transplantation. We found that the monocyte-derived macrophages primarily exhibited a proinflammatory phenotype that dominated the whole DiCM pathological process and impaired cardiac function. In contrast, cardiac resident macrophages were vulnerable to doxorubicin insult. The survived resident macrophages exhibited enhanced proliferation and conferred a reparative role. Global or myeloid specifically ablation of SR-A1 (class A1 scavenger receptor) inhibited proliferation of cardiac resident reparative macrophages and, therefore, exacerbated cardiomyopathy in DiCM mice. Importantly, the detrimental effect of macrophage SR-A1 deficiency was confirmed by transplantation of bone marrow. At the mechanistic level, we show that c-Myc (Avian myelocytomatosis virus oncogene cellular homolog), a key transcriptional factor for the SR-A1-P38-SIRT1 (Sirtuin 1) pathway, mediated the effect of SR-A1 in reparative macrophage proliferation in DiCM.

Conclusions: The SR-A1-c-Myc axis may represent a promising target to treat DiCM through augmentation of cardiac resident reparative macrophage proliferation.

Keywords: cardiomyopathy; doxorubicin; inflammation; macrophage; monocyte.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CX3C Chemokine Receptor 1 / genetics
  • CX3C Chemokine Receptor 1 / metabolism
  • Cardiomyopathy, Dilated / chemically induced
  • Cardiomyopathy, Dilated / enzymology*
  • Cardiomyopathy, Dilated / pathology
  • Cardiomyopathy, Dilated / prevention & control
  • Cell Proliferation*
  • Cell Self Renewal*
  • Cells, Cultured
  • Disease Models, Animal
  • Doxorubicin
  • Female
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Macrophages / enzymology*
  • Macrophages / pathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardium / enzymology*
  • Myocardium / pathology
  • Phenotype
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Scavenger Receptors, Class A / deficiency
  • Scavenger Receptors, Class A / genetics
  • Scavenger Receptors, Class A / metabolism*
  • Signal Transduction
  • Ventricular Remodeling

Substances

  • CX3C Chemokine Receptor 1
  • Cx3cr1 protein, mouse
  • Msr1 protein, mouse
  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • Scavenger Receptors, Class A
  • Green Fluorescent Proteins
  • Doxorubicin