Cardiomyocytes stimulate angiogenesis after ischemic injury in a ZEB2-dependent manner

  • The disruption in blood supply due to myocardial infarction is a critical determinant for infarct size and subsequent deterioration in function. The identification of factors that enhance cardiac repair by the restoration of the vascular network is, therefore, of great significance. Here, we show that the transcription factor Zinc finger E-box-binding homeobox 2 (ZEB2) is increased in stressed cardiomyocytes and induces a cardioprotective cross-talk between cardiomyocytes and endothelial cells to enhance angiogenesis after ischemia. Single-cell sequencing indicates ZEB2 to be enriched in injured cardiomyocytes. Cardiomyocyte-specific deletion of ZEB2 results in impaired cardiac contractility and infarct healing post-myocardial infarction (post-MI), while cardiomyocyte-specific ZEB2 overexpression improves cardiomyocyte survival and cardiac function. We identified Thymosin β4 (TMSB4) and Prothymosin α (PTMA) as main paracrine factors released from cardiomyocytes to stimulate angiogenesis by enhancing endothelial cell migration, and whose regulation is validated in our in vivo models. Therapeutic delivery of ZEB2 to cardiomyocytes in the infarcted heart induces the expression of TMSB4 and PTMA, which enhances angiogenesis and prevents cardiac dysfunction. These findings reveal ZEB2 as a beneficial factor during ischemic injury, which may hold promise for the identification of new therapies.
Metadaten
Author:Monika M. GladkaORCiD, Arwa KohelaORCiD, Bas Molenaar, Danielle Versteeg, Lieneke Kooijman, Jantine Monshouwer-Kloots, Veerle KremerORCiD, Harmjan R. VosORCiD, Manon M. H. HuibersORCiD, Jody J. HaighORCiD, Danny HuylebroeckORCiD, Reinier BoonORCiDGND, Mauro GiaccaORCiDGND, Eva van RooijORCiD
URN:urn:nbn:de:hebis:30:3-692842
DOI:https://doi.org/10.1038/s41467-020-20361-3
ISSN:2041-1723
Parent Title (English):Nature Communications
Publisher:Nature Publishing Group UK
Place of publication:[London]
Document Type:Article
Language:English
Date of Publication (online):2021/01/04
Date of first Publication:2021/01/04
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2024/03/11
Tag:Angiogenesis; Myocardial infarction
Volume:12.2021
Issue:art. 84
Article Number:84
Page Number:16
First Page:1
Last Page:16
Note:
This work was supported by the Leducq Foundation (14CVD04; to E.v.R.), the European Research Council under the European Union’s Seventh Framework Programme (ERC Grant Agreement CoG 615708 MICARUS; to E.v.R.) and Belspo IAPVII-07 Devrepair (to D.H. and J.J.H.).
Note:
Data availability

The authors declare that the main data supporting the findings of this study are available within the article and its Supplementary Information file. All sequencing data that support the findings of this study have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (GEO) and are accessible through the GEO Series accession number GSE146285 (for SCS data) and GSE151638 (for Zeb2 cKO RNA-seq data). The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE [1] partner repository with the dataset identifier PXD022212.

Source data are provided with this paper. Extra data are available from the corresponding author upon request. Source data are provided with this paper.
Institutes:Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International

OPUS4 Logo