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Original Research

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

Harmandeep Kaur, Mikito Takefuji, CY Ngai, Jorge Carvalho, Julia Bayer, Astrid Wietelmann, Ansgar Poetsch, Soraya Hölper, Simon J Conway, Helge Möllmann, Mario Looso, Christian Troidl, Stefan Offermanns, Nina Wettschureck
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https://doi.org/10.1161/CIRCRESAHA.116.308643
Circulation Research. 2016;CIRCRESAHA.116.308643
Originally published May 2, 2016
Harmandeep Kaur
Pharmacology, Max Planck Institute for Heart and Lung Research
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Mikito Takefuji
Cardiology, Nagoya University Graduate School of Medicine
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CY Ngai
Hong Kong Institute of Biotechnology
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Jorge Carvalho
Pharmacology, Max Planck Institute for Heart and Lung Research
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Julia Bayer
Bioinformatics Facility, Max Planck Institute for Heart and Lung Research
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Astrid Wietelmann
Nuclear Magnetic Resonance Imaging Facility, Max Planck Institute for Heart and Lung Research
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Ansgar Poetsch
Mass Spectrometry Group, Max Planck Institute for Heart and Lung Research
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Soraya Hölper
Mass Spectrometry Group, Max Planck Institute for Heart and Lung Research
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Simon J Conway
Pediatrics, Indiana University School of Medicine
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Helge Möllmann
Cardiology, Kerckhoff Heart and Thorax Center
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Mario Looso
Bioinformatics, Max Planck Institute for Heart and Lung Research
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Christian Troidl
Cardiology, Kerckhoff Heart and Thorax Center
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Stefan Offermanns
Pharmacology, Max Planck Institute for Heart and Lung Research
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Nina Wettschureck
Pharmacology, Max Planck Institute for Heart and Lung Research
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  • For correspondence: nina.wettschureck@mpi-bn.mpg.de
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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.

Conclusions: Modulation of the activated CF population is a promising approach to prevent adverse cardiac remodeling in response to angiotensin II and after myocardial infarction.

  • activated cardiac fibroblasts
  • periostin
  • myocardial infarction
  • myocardial fibrosis
  • cardiac failure
  • fibroblasts
  • heart failure
  • Received March 1, 2016.
  • Revision received April 27, 2016.
  • Accepted April 29, 2016.
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    Targeted Ablation of Periostin-Expressing Activated Fibroblasts Prevents Adverse Cardiac Remodeling in Mice
    Harmandeep Kaur, Mikito Takefuji, CY Ngai, Jorge Carvalho, Julia Bayer, Astrid Wietelmann, Ansgar Poetsch, Soraya Hölper, Simon J Conway, Helge Möllmann, Mario Looso, Christian Troidl, Stefan Offermanns and Nina Wettschureck
    Circulation Research. 2016;CIRCRESAHA.116.308643, originally published May 2, 2016
    https://doi.org/10.1161/CIRCRESAHA.116.308643

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    Targeted Ablation of Periostin-Expressing Activated Fibroblasts Prevents Adverse Cardiac Remodeling in Mice
    Harmandeep Kaur, Mikito Takefuji, CY Ngai, Jorge Carvalho, Julia Bayer, Astrid Wietelmann, Ansgar Poetsch, Soraya Hölper, Simon J Conway, Helge Möllmann, Mario Looso, Christian Troidl, Stefan Offermanns and Nina Wettschureck
    Circulation Research. 2016;CIRCRESAHA.116.308643, originally published May 2, 2016
    https://doi.org/10.1161/CIRCRESAHA.116.308643
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Subjects

  • Heart Failure and Cardiac Disease
    • Myocardial Infarction
    • Remodeling
    • Hypertrophy
    • Heart Failure

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