Author
Listed:
- Monika M. Gladka
(Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Centre)
- Arwa Kohela
(Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Centre)
- Bas Molenaar
(Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Centre)
- Danielle Versteeg
(Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Centre
University Medical Center)
- Lieneke Kooijman
(Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Centre)
- Jantine Monshouwer-Kloots
(Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Centre)
- Veerle Kremer
(Amsterdam University Medical Center VU
Amsterdam University Medical Center)
- Harmjan R. Vos
(University Medical Center)
- Manon M. H. Huibers
(University Medical Centre Utrecht)
- Jody J. Haigh
(University of Manitoba)
- Danny Huylebroeck
(Erasmus University Medical Centre
University of Leuven)
- Reinier A. Boon
(Amsterdam University Medical Center VU
Goethe University
German Center for Cardiovascular Research (DZHK))
- Mauro Giacca
(School of Cardiovascular Medicine and Sciences, King’s College London)
- Eva Rooij
(Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Centre
University Medical Center)
Abstract
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.
Suggested Citation
Monika M. Gladka & Arwa Kohela & Bas Molenaar & Danielle Versteeg & Lieneke Kooijman & Jantine Monshouwer-Kloots & Veerle Kremer & Harmjan R. Vos & Manon M. H. Huibers & Jody J. Haigh & Danny Huylebro, 2021.
"Cardiomyocytes stimulate angiogenesis after ischemic injury in a ZEB2-dependent manner,"
Nature Communications, Nature, vol. 12(1), pages 1-16, December.
Handle:
RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20361-3
DOI: 10.1038/s41467-020-20361-3
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Citations
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Cited by:
- Xin Zhang & Yi-Peng Gao & Wen-Sheng Dong & Kang Li & Yu-Xin Hu & Yun-Jia Ye & Can Hu, 2024.
"FNDC4 alleviates cardiac ischemia/reperfusion injury through facilitating HIF1α-dependent cardiomyocyte survival and angiogenesis in male mice,"
Nature Communications, Nature, vol. 15(1), pages 1-17, December.
- Wenya Ma & Yanan Tian & Leping Shi & Jing Liang & Qimeng Ouyang & Jianglong Li & Hongyang Chen & Hongyue Sun & Haoyu Ji & Xu Liu & Wei Huang & Xinlu Gao & Xiaoyan Jin & Xiuxiu Wang & Yining Liu & Yang, 2024.
"N-Acetyltransferase 10 represses Uqcr11 and Uqcrb independently of ac4C modification to promote heart regeneration,"
Nature Communications, Nature, vol. 15(1), pages 1-19, December.
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