TY  - JOUR
A1  - Gladka, Monika M.
A1  - Kohela, Arwa
A1  - Molenaar, Bas
A1  - Versteeg, Danielle
A1  - Kooijman, Lieneke
A1  - Monshouwer-Kloots, Jantine
A1  - Kremer, Veerle
A1  - Vos, Harmjan R.
A1  - Huibers, Manon M. H.
A1  - Haigh, Jody J.
A1  - Huylebroeck, Danny
A1  - Boon, Reinier
A1  - Giacca, Mauro
A1  - Rooij, Eva van
T1  - Cardiomyocytes stimulate angiogenesis after ischemic injury in a ZEB2-dependent manner
T2  - Nature Communications
N2  - 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.
KW  - Angiogenesis
KW  - Myocardial infarction
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/69284
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-692842
SN  - 2041-1723
N1  - 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.).
N1  - 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.
VL  - 12.2021
IS  - art. 84
SP  - 1
EP  - 16
PB  - Nature Publishing Group UK
CY  - [London]
ER  -