DNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
19 Jan 2024
19 Jan 2024
Historique:
received:
23
12
2022
accepted:
27
10
2023
medline:
20
1
2024
pubmed:
20
1
2024
entrez:
19
1
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38242884
doi: 10.1038/s41467-023-43003-w
pii: 10.1038/s41467-023-43003-w
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
606Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : SFB 1366
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : SFB 1531
Informations de copyright
© 2023. The Author(s).
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