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

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.

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 Creators:
Kaur, Harmandeep1, Author           
Takefuji, Mikito1, Author           
Ngai, Ching-Yuen1, Author           
Carvalho, Jorge1, Author           
Bayer, Julia2, Author           
Wietelmann, Astrid3, Author           
Poetsch, Ansgar4, Author           
Hoelper, Soraya5, Author           
Conway, Simon J., Author
Moellmann, Helge, Author
Looso, Mario2, Author           
Troidl, Christian, Author
Offermanns, Stefan1, Author           
Wettschureck, Nina1, Author           
Affiliations:
1Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591696              
2Bioinformatics, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591704              
3Small Animal Magnetic Resonance Imaging, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591708              
4Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591705              
5Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591698              

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Free keywords: ACUTE MYOCARDIAL-INFARCTION; TO-MESENCHYMAL TRANSITION; DOMAIN RECEPTOR 2; ANGIOTENSIN-II; EXTRACELLULAR-MATRIX; CELL; HEART; FIBROSIS; REPAIR; COLLAGENCardiovascular System & Cardiology; Hematology; extracellular matrix; fibroblast; heart failure; myocardial infarction; phenotype;
 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.

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Language(s): eng - English
 Dates: 2016
 Publication Status: Published in print
 Pages: 18
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Degree: -

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Title: CIRCULATION RESEARCH
Source Genre: Journal
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Publ. Info: TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA : LIPPINCOTT WILLIAMS & WILKINS
Pages: - Volume / Issue: 118 (12) Sequence Number: - Start / End Page: 1906 - + Identifier: ISSN: 0009-7330