RNA-Binding Proteins Regulate Post-Transcriptional Responses to TGF-β to Coordinate Function and Mesenchymal Activation of Murine Endothelial Cells.

Autor:	Wardman R; Department of Cardiovascular Physiology (R.W., M.K., I.P., S.H., S.G., J.H.), European Center for Angioscience (ECAS), Medical Faculty Mannheim of Heidelberg University, Germany.; German Center for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim (R.W., M.K., S.H., S.G., G.D., J.H.)., Keles M; Department of Cardiovascular Physiology (R.W., M.K., I.P., S.H., S.G., J.H.), European Center for Angioscience (ECAS), Medical Faculty Mannheim of Heidelberg University, Germany.; German Center for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim (R.W., M.K., S.H., S.G., G.D., J.H.)., Pachkiv I; Department of Cardiovascular Physiology (R.W., M.K., I.P., S.H., S.G., J.H.), European Center for Angioscience (ECAS), Medical Faculty Mannheim of Heidelberg University, Germany., Hemanna S; Department of Cardiovascular Physiology (R.W., M.K., I.P., S.H., S.G., J.H.), European Center for Angioscience (ECAS), Medical Faculty Mannheim of Heidelberg University, Germany.; German Center for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim (R.W., M.K., S.H., S.G., G.D., J.H.)., Grein S; Department of Cardiovascular Physiology (R.W., M.K., I.P., S.H., S.G., J.H.), European Center for Angioscience (ECAS), Medical Faculty Mannheim of Heidelberg University, Germany.; German Center for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim (R.W., M.K., S.H., S.G., G.D., J.H.)., Schwarz J; Proteomics Core Facility, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany (J.S., F.S.)., Stein F; Proteomics Core Facility, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany (J.S., F.S.)., Ola R; Cardiovascular Pharmacology (R.O.), European Center for Angioscience (ECAS), Medical Faculty Mannheim of Heidelberg University, Germany., Dobreva G; Cardiovascular Genomics and Epigenomics (G.D.), European Center for Angioscience (ECAS), Medical Faculty Mannheim of Heidelberg University, Germany.; German Center for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim (R.W., M.K., S.H., S.G., G.D., J.H.)., Hentze MW; European Molecular Biology Laboratory (EMBL), Heidelberg, Germany (M.W.H.)., Heineke J; Department of Cardiovascular Physiology (R.W., M.K., I.P., S.H., S.G., J.H.), European Center for Angioscience (ECAS), Medical Faculty Mannheim of Heidelberg University, Germany.; German Center for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim (R.W., M.K., S.H., S.G., G.D., J.H.).
Jazyk:	angličtina
Zdroj:	Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2023 Oct; Vol. 43 (10), pp. 1967-1989. Date of Electronic Publication: 2023 Aug 31.
DOI:	10.1161/ATVBAHA.123.319925
Abstrakt:	Background: Endothelial cells (ECs) are primed to respond to various signaling cues. For example, TGF (transforming growth factor)-β has major effects on EC function and phenotype by driving ECs towards a more mesenchymal state (ie, triggering endothelial to mesenchymal activation), a dynamic process associated with cardiovascular diseases. Although transcriptional regulation triggered by TGF-β in ECs is well characterized, post-transcriptional regulatory mechanisms induced by TGF-β remain largely unknown. Methods: Using RNA interactome capture, we identified global TGF-β driven changes in RNA-binding proteins in ECs. We investigated specific changes in the RNA-binding patterns of hnRNP H1 (heterogeneous nuclear ribonucleoprotein H1) and Csde1 (cold shock domain containing E1) using RNA immunoprecipitation and overlapped this with RNA-sequencing data after knockdown of either protein for functional insight. Using a modified proximity ligation assay, we visualized the specific interactions between hnRNP H1 and Csde1 and target RNAs in situ both in vitro and in mouse heart sections. Results: Characterization of TGF-β-regulated RBPs (RNA-binding proteins) revealed hnRNP H1 and Csde1 as key regulators of the cellular response to TGF-β at the post-transcriptional level, with loss of either protein-promoting mesenchymal activation in ECs. We found that TGF-β drives an increase in binding of hnRNP H1 to its target RNAs, offsetting mesenchymal activation, but a decrease in Csde1 RNA-binding, facilitating this process. Both, hnRNP H1 and Csde1, dynamically bind and regulate specific subsets of mRNAs related to mesenchymal activation and endothelial function. Conclusions: Together, we show that RBPs play a key role in the endothelial response to TGF-β stimulation at the post-transcriptional level and that the RBPs hnRNP H1 and Csde1 serve to maintain EC function and counteract mesenchymal activation. We propose that TGF-β profoundly modifies RNA-protein interaction entailing feedback and feed-forward control at the post-transcriptional level, to fine-tune mesenchymal activation in ECs. Competing Interests: Disclosures None.
Databáze:	MEDLINE
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