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

MPS-Authors
/persons/resource/persons224181

Kaur,  Harmandeep
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224197

Takefuji,  Mikito
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224183

Ngai,  Ching-Yuen
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224173

Carvalho,  Jorge
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224380

Bayer,  Julia
Bioinformatics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224397

Wietelmann,  Astrid
Small Animal Magnetic Resonance Imaging, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224390

Poetsch,  Ansgar
Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224064

Hoelper,  Soraya
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224384

Looso,  Mario
Bioinformatics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224185

Offermanns,  Stefan
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224211

Wettschureck,  Nina
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Citation

Kaur, H., Takefuji, M., Ngai, C.-Y., Carvalho, J., Bayer, J., Wietelmann, A., et al. (2016). Targeted Ablation of Periostin-Expressing Activated Fibroblasts Prevents Adverse Cardiac Remodeling in Mice. CIRCULATION RESEARCH, 118(12), 1906-+. doi:10.1161/CIRCRESAHA.116.308643.


Cite as: http://hdl.handle.net/21.11116/0000-0001-C130-E
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 bacterial artificial chromosome-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 prohypertrophic 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.