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

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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

Original languageEnglish
Article number26
JournalBasic Research in Cardiology
Volume116
Issue number1
DOIs
PublishedDec 2021

Bibliographical note

Funding Information: Open Access funding enabled and organized by Projekt DEAL. This study was supported by the Deutsche Forschungsgemeinschaft through the Cluster of Excellence Rebirth (EXC 62/1 and EXC 62/3 to K.C.W., J.B., and J.H.), the Heisenberg Program (HE 3658/6–1 and 2 to J.H.), the research grants HE 3658/9–1 and SFB 1366/1, A06 (to J.H.) along with National Institutes of Health grant NIH R01 HL148165 (to S.J.C.). X.W. was supported by the China Scholarship Council grant 201608080061. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

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.

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