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Fibroblast GATA-4 and GATA-6 promote myocardial adaptation to pressure overload by enhancing cardiac angiogenesis

Heart failure due to high blood pressure or ischemic injury remains a major problem for millions of patients worldwide. Despite enormous advances in deciphering the molecular mechanisms underlying heart failure progression, the cell-type specific adaptations and especially intercellular signaling re...

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Hauptverfasser: Dittrich, Gesine M. (VerfasserIn) , Froese, Natali (VerfasserIn) , Wang, Xue (VerfasserIn) , Kroeger, Hannah (VerfasserIn) , Wang, Honghui (VerfasserIn) , Szaroszyk, Malgorzata (VerfasserIn) , Malek Mohammadi, Mona (VerfasserIn) , Cordero, Julio (VerfasserIn) , Keles, Merve (VerfasserIn) , Korf-Klingebiel, Mortimer (VerfasserIn) , Wollert, Kai C. (VerfasserIn) , Geffers, Robert (VerfasserIn) , Mayr, Manuel (VerfasserIn) , Conway, Simon J. (VerfasserIn) , Dobreva, Gergana (VerfasserIn) , Bauersachs, Johann (VerfasserIn) , Heineke, Jörg (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 19 April 2021
In: Basic research in cardiology
Year: 2021, Jahrgang: 116, Pages: 1-19
ISSN:1435-1803
DOI:10.1007/s00395-021-00862-y
Online-Zugang:Verlag, kostenfrei, Volltext: https://doi.org/10.1007/s00395-021-00862-y
Verlag, kostenfrei, Volltext: https://link.springer.com/10.1007/s00395-021-00862-y
Volltext
Verfasserangaben:Gesine M.Dittrich, Natali Froese, Xue Wang, Hannah Kroeger, Honghui Wang, Malgorzata Szaroszyk, Mona Malek-Mohammadi, Julio Cordero, Merve Keles, Mortimer Korf-Klingebiel, Kai C.Wollert, Robert Geffers, Manuel Mayr, Simon J.Conway, Gergana Dobreva, Johann Bauersachs, Joerg Heineke
Beschreibung
Zusammenfassung:Heart failure due to high blood pressure or ischemic injury remains a major problem for millions of patients worldwide. Despite enormous advances in deciphering the molecular mechanisms underlying heart failure progression, the cell-type specific adaptations and especially intercellular signaling remain poorly understood. Cardiac fibroblasts express high levels of cardiogenic transcription factors such as GATA-4 and GATA-6, but their role in fibroblasts during stress is not known. Here, we show that fibroblast GATA-4 and GATA-6 promote adaptive remodeling in pressure overload induced cardiac hypertrophy. Using a mouse model with specific single or double deletion of Gata4 and Gata6 in stress activated fibroblasts, we found a reduced myocardial capillarization in mice with Gata4/6 double deletion following pressure overload, while single deletion of Gata4 or Gata6 had no effect. Importantly, we confirmed the reduced angiogenic response using an in vitro co-culture system with Gata4/6 deleted cardiac fibroblasts and endothelial cells. A comprehensive RNA-sequencing analysis revealed an upregulation of anti-angiogenic genes upon Gata4/6 deletion in fibroblasts, and siRNA mediated downregulation of these genes restored endothelial cell growth. In conclusion, we identified a novel role for the cardiogenic transcription factors GATA-4 and GATA-6 in heart fibroblasts, where both proteins act in concert to promote myocardial capillarization and heart function by directing intercellular crosstalk.
Beschreibung:Gesehen am 15.08.2023
Beschreibung:Online Resource
ISSN:1435-1803
DOI:10.1007/s00395-021-00862-y

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