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- Title
Fibroblast GATA‑4 and GATA‑6 promote myocardial adaptation to pressure overload by enhancing cardiac angiogenesis.
- Authors
Dittrich, Gesine M.; Froese, Natali; Xue Wang; Kroeger, Hannah; Honghui Wang; Szaroszyk, Malgorzata; Malek‑Mohammadi, Mona; Cordero, Julio; Keles, Merve; Korf‑Klingebiel, Mortimer; Wollert, Kai C.; Gefers, Robert; Mayr, Manuel; Conway, Simon J.; Dobreva, Gergana; Bauersachs, Johann; Heineke, Joerg
- 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 specifc adaptations and especially intercellular signaling remain poorly understood. Cardiac fbroblasts express high levels of cardiogenic transcription factors such as GATA-4 and GATA-6, but their role in fbroblasts during stress is not known. Here, we show that fbroblast GATA-4 and GATA-6 promote adaptive remodeling in pressure overload induced cardiac hypertrophy. Using a mouse model with specifc single or double deletion of Gata4 and Gata6 in stress activated fbroblasts, 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 efect. Importantly, we confrmed the reduced angiogenic response using an in vitro co-culture system with Gata4/6 deleted cardiac fbroblasts and endothelial cells. A comprehensive RNA-sequencing analysis revealed an upregulation of anti-angiogenic genes upon Gata4/6 deletion in fbroblasts, and siRNA mediated downregulation of these genes restored endothelial cell growth. In conclusion, we identifed a novel role for the cardiogenic transcription factors GATA-4 and GATA-6 in heart fbroblasts, where both proteins act in concert to promote myocardial capillarization and heart function by directing intercellular crosstalk.
- Publication
Basic Research in Cardiology, 2021, Vol 116, Issue 1, p1
- ISSN
0300-8428
- Publication type
Article
- DOI
10.1007/s00395-021-00862-y