DNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts

  • Hematopoietic mutations in epigenetic regulators like DNA methyltransferase 3 alpha (DNMT3A), play a pivotal role in driving clonal hematopoiesis of indeterminate potential (CHIP), and are associated with unfavorable outcomes in patients suffering from heart failure (HF). However, the precise interactions between CHIP-mutated cells and other cardiac cell types remain unknown. Here, we identify fibroblasts as potential partners in interactions with CHIP-mutated monocytes. We used combined transcriptomic data derived from peripheral blood mononuclear cells of HF patients, both with and without CHIP, and cardiac tissue. We demonstrate that inactivation of DNMT3A in macrophages intensifies interactions with cardiac fibroblasts and increases cardiac fibrosis. DNMT3A inactivation amplifies the release of heparin-binding epidermal growth factor-like growth factor, thereby facilitating activation of cardiac fibroblasts. These findings identify a potential pathway of DNMT3A CHIP-driver mutations to the initiation and progression of HF and may also provide a compelling basis for the development of innovative anti-fibrotic strategies.

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Author:Mariana ShumliakivskaORCiD, Guillermo LuxánORCiD, Inga HemmerlingGND, Marina SchellerORCiDGND, Xue LiGND, Carsten Müller-TidowORCiDGND, Bianca SchuhmacherGND, Zhengwu SunORCiD, Andreas DendorferORCiDGND, Alisa Debes, Simone F. GlaserORCiDGND, Marion Muhly-Reinholz, Klara KirschbaumORCiDGND, Jedrzej HoffmannORCiDGND, Eike NagelORCiDGND, Valentina O. PuntmannORCiD, Sebastian CremerORCiDGND, Florian LeuschnerORCiDGND, Wesley Tyler AbplanalpORCiD, David JohnORCiDGND, Andreas M. ZeiherORCiDGND, Stefanie DimmelerORCiDGND
URN:urn:nbn:de:hebis:30:3-855530
DOI:https://doi.org/10.1038/s41467-023-43003-w
ISSN:2041-1723
Parent Title (English):Nature Communications
Publisher:Nature Publishing Group UK
Place of publication:London
Document Type:Article
Language:English
Date of Publication (online):2024/01/19
Date of first Publication:2024/01/19
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2024/05/13
Volume:15
Issue:Article number 606
Article Number:606
Page Number:20
Institutes:Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International