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

Clemens Duerrschmid, Jeffrey R. Crawford, Erin L. Reineke, George Taffet, Jo Ann Trial, Mark L. Entman, Sandra B. Haudek

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)59-67
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume57
Issue number1
DOIs
StatePublished - Apr 2013

Keywords

  • Angiotensin-II
  • Fibrosis
  • Hypertrophy
  • Inflammation
  • Monocytes
  • Tumor necrosis factor-alpha

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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