Monocytic fibroblast precursors mediate fibrosis in angiotensin-II-induced cardiac hypertrophy

J Mol Cell Cardiol. 2010 Sep;49(3):499-507. doi: 10.1016/j.yjmcc.2010.05.005. Epub 2010 May 19.


Angiotensin-II (Ang-II) is an autacoid generated as part of the pathophysiology of cardiac hypertrophy and failure. In addition to its role in cardiac and smooth muscle contraction and salt retention, it was shown to play a major role in the cardiac interstitial inflammatory response and fibrosis accompanying cardiac failure. In this study, we examined a model of Ang-II infusion to clarify the early cellular mechanisms linking interstitial fibrosis with the onset of the tissue inflammatory response. Continuous infusion of Ang-II resulted in increased deposition of collagen in the heart. Ang-II infusion also resulted in the appearance of distinctive small, spindle-shaped, bone marrow-derived CD34(+)/CD45(+) fibroblasts that expressed collagen type I and the cardiac fibroblast marker DDR2 while structural fibroblasts were CD34(-)/CD45(-). Genetic deletion of monocyte chemoattractant protein (MCP)-1 (MCP-1-KO mice) prevented the Ang-II-induced cardiac fibrosis and the appearance of CD34(+)/CD45(+) fibroblasts. Real-time PCR in Ang-II-treated hearts revealed a striking induction of types I and III collagen, TGF-beta1, and TNF mRNA expression; this was obviated in Ang-II-infused MCP-1-KO hearts. In both wild-type and MCP-1-KO mice, Ang-II infusion resulted in cardiac hypertrophy, increased systolic function and hypertension which were not significantly different between the WT and MCP-1-KO mice over the 6-week course of infusion. In conclusion, the development of Ang-II-induced non-adaptive fibrosis in the heart required induction of MCP-1, which modulated the uptake and differentiation of a CD34(+)/CD45(+) fibroblast precursor population. In contrast to the inflammatory and fibrotic response, the hemodynamic response to Ang-II was not affected by MCP-1 in the first 6weeks.

Publication types

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

MeSH terms

  • Angiotensin II / pharmacology*
  • Animals
  • Cardiomegaly / chemically induced
  • Cardiomegaly / metabolism
  • Cardiomegaly / pathology*
  • Chemokine CCL2 / physiology*
  • Collagen / genetics
  • Collagen / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibrosis
  • Hypertension / chemically induced
  • Hypertension / metabolism
  • Hypertension / pathology
  • Lung Diseases, Interstitial / chemically induced
  • Lung Diseases, Interstitial / metabolism
  • Lung Diseases, Interstitial / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Vasoconstrictor Agents / pharmacology*


  • Ccl2 protein, mouse
  • Chemokine CCL2
  • RNA, Messenger
  • Vasoconstrictor Agents
  • Angiotensin II
  • Collagen