CCR2 mediates the uptake of bone marrow-derived fibroblast precursors in angiotensin II-induced cardiac fibrosis

Am J Physiol Heart Circ Physiol. 2011 Aug;301(2):H538-47. doi: 10.1152/ajpheart.01114.2010. Epub 2011 May 13.


Angiotensin II plays an important role in the development of cardiac hypertrophy and fibrosis, but the underlying cellular and molecular mechanisms are not completely understood. Recent studies have shown that bone marrow-derived fibroblast precursors are involved in the pathogenesis of cardiac fibrosis. Since bone marrow-derived fibroblast precursors express chemokine receptor, CCR2, we tested the hypothesis that CCR2 mediates the recruitment of fibroblast precursors into the heart, causing angiotensin II-induced cardiac fibrosis. Wild-type and CCR2 knockout mice were infused with angiotensin II at 1,500 ng·kg(-1)·min(-1). Angiotensin II treatment resulted in elevated blood pressure and cardiac hypertrophy that were not significantly different between wild-type and CCR2 knockout mice. Angiotensin II treatment of wild-type mice caused prominent cardiac fibrosis and accumulation of bone marrow-derived fibroblast precursors expressing the hematopoietic markers, CD34 and CD45, and the mesenchymal marker, collagen I. However, angiotensin II-induced cardiac fibrosis and accumulation of bone marrow-derived fibroblast precursors in the heart were abrogated in CCR2 knockout mice. Furthermore, angiotensin II treatment of wild-type mice increased the levels of collagen I, fibronectin, and α-smooth muscle actin in the heart, whereas these changes were not observed in the heart of angiotensin II-treated CCR2 knockout mice. Functional studies revealed that the reduction of cardiac fibrosis led to an impairment of cardiac systolic function and left ventricular dilatation in angiotensin II-treated CCR2 knockout mice. Our data demonstrate that CCR2 plays a pivotal role in the pathogenesis of angiotensin II-induced cardiac fibrosis through regulation of bone marrow-derived fibroblast precursors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Angiotensin II*
  • Animals
  • Biomarkers / metabolism
  • Blood Pressure
  • Bone Marrow Cells / metabolism*
  • Cardiomegaly / chemically induced
  • Cardiomegaly / metabolism
  • Cell Movement*
  • Disease Models, Animal
  • Fibroblasts / metabolism*
  • Fibrosis
  • Heart Diseases / chemically induced
  • Heart Diseases / diagnostic imaging
  • Heart Diseases / metabolism
  • Heart Diseases / physiopathology
  • Heart Diseases / prevention & control*
  • Heart Rate
  • Hypertension / chemically induced
  • Hypertension / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Receptors, CCR2 / deficiency
  • Receptors, CCR2 / genetics
  • Receptors, CCR2 / metabolism*
  • Stem Cells / metabolism*
  • Stroke Volume
  • Time Factors
  • Ultrasonography
  • Ventricular Dysfunction, Left / chemically induced
  • Ventricular Dysfunction, Left / metabolism
  • Ventricular Function, Left
  • Ventricular Remodeling


  • Biomarkers
  • Ccr2 protein, mouse
  • Receptors, CCR2
  • Angiotensin II