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

Mariana Shumliakivska, Guillermo Luxán, Inga Hemmerling, Marina Scheller, Xue Li, Carsten Müller-Tidow, Bianca Schuhmacher, Zhengwu Sun, Andreas Dendorfer, Alisa Debes, Simone-Franziska Glaser, Marion Muhly-Reinholz, Klara Kirschbaum, Jedrzej Hoffmann, Eike Nagel, Valentina O. Puntmann, Sebastian Cremer, Florian Leuschner, Wesley Tyler Abplanalp, David John, Andreas M. Zeiher and Stefanie Dimmeler ()
Additional contact information
Mariana Shumliakivska: Institute for Cardiovascular Regeneration, Goethe University Frankfurt
Guillermo Luxán: Institute for Cardiovascular Regeneration, Goethe University Frankfurt
Inga Hemmerling: University Hospital Heidelberg, University of Heidelberg
Marina Scheller: University of Heidelberg
Xue Li: University Hospital Heidelberg, University of Heidelberg
Carsten Müller-Tidow: University of Heidelberg
Bianca Schuhmacher: Institute for Cardiovascular Regeneration, Goethe University Frankfurt
Zhengwu Sun: Walter-Brendel-Centre of Experimental Medicine, Hospital of the Ludwig-Maximilians-University Munich
Andreas Dendorfer: Walter-Brendel-Centre of Experimental Medicine, Hospital of the Ludwig-Maximilians-University Munich
Alisa Debes: Institute for Cardiovascular Regeneration, Goethe University Frankfurt
Simone-Franziska Glaser: Institute for Cardiovascular Regeneration, Goethe University Frankfurt
Marion Muhly-Reinholz: Institute for Cardiovascular Regeneration, Goethe University Frankfurt
Klara Kirschbaum: University Hospital Frankfurt
Jedrzej Hoffmann: German Center of Cardiovascular Research (DZHK), Partner Site Rhine/Main
Eike Nagel: German Center of Cardiovascular Research (DZHK), Partner Site Rhine/Main
Valentina O. Puntmann: German Center of Cardiovascular Research (DZHK), Partner Site Rhine/Main
Sebastian Cremer: Institute for Cardiovascular Regeneration, Goethe University Frankfurt
Florian Leuschner: University Hospital Heidelberg, University of Heidelberg
Wesley Tyler Abplanalp: Institute for Cardiovascular Regeneration, Goethe University Frankfurt
David John: Institute for Cardiovascular Regeneration, Goethe University Frankfurt
Andreas M. Zeiher: Institute for Cardiovascular Regeneration, Goethe University Frankfurt
Stefanie Dimmeler: Institute for Cardiovascular Regeneration, Goethe University Frankfurt

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-023-43003-w

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