Targeted Ablation of Periostin-Expressing Activated Fibroblasts Prevents Adverse Cardiac Remodeling in Mice

Harmandeep Kaur, Mikito Takefuji, C. Y. Ngai, Jorge Carvalho, Julia Bayer, Astrid Wietelmann, Ansgar Poetsch, Soraya Hoelper, Simon Conway, Helge Möllmann, Mario Looso, Christian Troidl, Stefan Offermanns, Nina Wettschureck

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

RATIONALE:: Activated cardiac fibroblasts (CF) are crucial players in the cardiac damage response; excess fibrosis, however, may result in myocardial stiffening and heart failure development. Inhibition of activated CF has been suggested as a therapeutic strategy in cardiac disease, but whether this truly improves cardiac function, is unclear. OBJECTIVE:: To study the effect of CF ablation on cardiac remodeling. METHODS AND RESULTS:: We characterized subgroups of murine CF by single cell expression analysis and identified periostin as the marker showing the highest correlation to an activated CF phenotype. We generated BAC-transgenic mice allowing tamoxifen-inducible Cre expression in periostin-positive cells as well as their diphtheria toxin-mediated ablation. In the healthy heart, periostin expression was restricted to valvular fibroblasts; ablation of this population did not affect cardiac function. After chronic angiotensin II exposure, ablation of activated CF resulted in significantly reduced cardiac fibrosis and improved cardiac function. After myocardial infarction, ablation of periostin-expressing CF resulted in reduced fibrosis without compromising scar stability, and cardiac function was significantly improved. Single cell transcriptional analysis revealed reduced CF activation, but increased expression of pro-hypertrophic factors in cardiac macrophages and cardiomyocytes, resulting in localized cardiomyocyte hypertrophy. CONCLUSION:: Modulation of the activated CF population is a promising approach to prevent adverse cardiac remodeling in response to angiotensin II and after myocardial infarction.

Original languageEnglish (US)
JournalCirculation Research
DOIs
StateAccepted/In press - May 3 2016

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Fibroblasts
Single-Cell Analysis
Fibrosis
Cardiac Myocytes
Angiotensin II
Heart Failure
Myocardial Infarction
Diphtheria Toxin
Tamoxifen
Hypertrophy
Transgenic Mice
Population
Cicatrix
Heart Diseases
Macrophages
Phenotype

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Kaur, H., Takefuji, M., Ngai, C. Y., Carvalho, J., Bayer, J., Wietelmann, A., ... Wettschureck, N. (Accepted/In press). Targeted Ablation of Periostin-Expressing Activated Fibroblasts Prevents Adverse Cardiac Remodeling in Mice. Circulation Research. https://doi.org/10.1161/CIRCRESAHA.116.308643

Targeted Ablation of Periostin-Expressing Activated Fibroblasts Prevents Adverse Cardiac Remodeling in Mice. / Kaur, Harmandeep; Takefuji, Mikito; Ngai, C. Y.; Carvalho, Jorge; Bayer, Julia; Wietelmann, Astrid; Poetsch, Ansgar; Hoelper, Soraya; Conway, Simon; Möllmann, Helge; Looso, Mario; Troidl, Christian; Offermanns, Stefan; Wettschureck, Nina.

In: Circulation Research, 03.05.2016.

Research output: Contribution to journalArticle

Kaur, H, Takefuji, M, Ngai, CY, Carvalho, J, Bayer, J, Wietelmann, A, Poetsch, A, Hoelper, S, Conway, S, Möllmann, H, Looso, M, Troidl, C, Offermanns, S & Wettschureck, N 2016, 'Targeted Ablation of Periostin-Expressing Activated Fibroblasts Prevents Adverse Cardiac Remodeling in Mice', Circulation Research. https://doi.org/10.1161/CIRCRESAHA.116.308643
Kaur, Harmandeep ; Takefuji, Mikito ; Ngai, C. Y. ; Carvalho, Jorge ; Bayer, Julia ; Wietelmann, Astrid ; Poetsch, Ansgar ; Hoelper, Soraya ; Conway, Simon ; Möllmann, Helge ; Looso, Mario ; Troidl, Christian ; Offermanns, Stefan ; Wettschureck, Nina. / Targeted Ablation of Periostin-Expressing Activated Fibroblasts Prevents Adverse Cardiac Remodeling in Mice. In: Circulation Research. 2016.
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AU - Bayer, Julia

AU - Wietelmann, Astrid

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