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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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Main Authors: Dittrich, Gesine M. (Author) , Froese, Natali (Author) , Wang, Xue (Author) , Kroeger, Hannah (Author) , Wang, Honghui (Author) , Szaroszyk, Malgorzata (Author) , Malek Mohammadi, Mona (Author) , Cordero, Julio (Author) , Keles, Merve (Author) , Korf-Klingebiel, Mortimer (Author) , Wollert, Kai C. (Author) , Geffers, Robert (Author) , Mayr, Manuel (Author) , Conway, Simon J. (Author) , Dobreva, Gergana (Author) , Bauersachs, Johann (Author) , Heineke, Jörg (Author)
Format: Article (Journal)
Language:English
Published: 19 April 2021
In: Basic research in cardiology
Year: 2021, Volume: 116, Pages: 1-19
ISSN:1435-1803
DOI:10.1007/s00395-021-00862-y
Online Access: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
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Author Notes: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
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Summary: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.
Item Description:Gesehen am 15.08.2023
Physical Description:Online Resource
ISSN:1435-1803
DOI:10.1007/s00395-021-00862-y

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