TNF receptor 1 signaling is critically involved in mediating angiotensin-II-induced cardiac fibrosis

J Mol Cell Cardiol. 2013 Apr:57:59-67. doi: 10.1016/j.yjmcc.2013.01.006. Epub 2013 Jan 18.


Angiotensin-II (Ang-II) is associated with many conditions involving heart failure and pathologic hypertrophy. Ang-II induces the synthesis of monocyte chemoattractant protein-1 that mediates the uptake of CD34(+)CD45(+) monocytic cells into the heart. These precursor cells differentiate into collagen-producing fibroblasts and are responsible for the Ang-II-induced development of non-adaptive cardiac fibrosis. In this study, we demonstrate that in vitro, using a human monocyte-to-fibroblast differentiation model, Ang-II required the presence of tumor necrosis factor-alpha (TNF) to induce fibroblast maturation from monocytes. In vivo, mice deficient in both TNF receptors did not develop cardiac fibrosis in response to 1week Ang-II infusion. We then subjected mice deficient in either TNF receptor 1 (TNFR1-KO) or TNF receptor 2 (TNFR2-KO) to continuous Ang-II infusion. Compared to wild-type, in TNFR1-KO, but not in TNFR2-KO hearts, collagen deposition was greatly attenuated, and markedly fewer CD34(+)CD45(+) cells were present. Quantitative RT-PCR demonstrated a striking reduction of key fibrosis-related, as well as inflammation-related mRNA expression in Ang-II-treated TNFR1-KO hearts. TNFR1-KO animals also developed less cardiac remodeling, cardiac hypertrophy, and hypertension compared to wild-type and TNFR2-KO in response to Ang-II. Our data suggest that TNF induced Ang-II-dependent cardiac fibrosis by signaling through TNFR1, which enhances the generation of monocytic fibroblast precursors in the heart.

Publication types

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

MeSH terms

  • Angiotensin II / physiology*
  • Animals
  • Cardiomegaly / metabolism*
  • Cardiomegaly / pathology
  • Cell Differentiation
  • Cell Size
  • Cells, Cultured
  • Coculture Techniques
  • Collagen / metabolism
  • Cytokines / genetics
  • Cytokines / metabolism
  • Fibrosis
  • Gene Expression
  • Humans
  • Inflammation Mediators / metabolism
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Myocardium / pathology
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / physiology
  • Myofibroblasts / metabolism
  • Myofibroblasts / pathology
  • Receptors, Tumor Necrosis Factor, Type I / metabolism*
  • Signal Transduction*
  • Transendothelial and Transepithelial Migration
  • Transforming Growth Factor beta1 / metabolism
  • Tumor Necrosis Factor-alpha / physiology


  • Cytokines
  • Inflammation Mediators
  • Receptors, Tumor Necrosis Factor, Type I
  • Tnfrsf1a protein, mouse
  • Transforming Growth Factor beta1
  • Tumor Necrosis Factor-alpha
  • Angiotensin II
  • Collagen