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

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 Huylebroeck, Reinier A. Boon, Mauro Giacca and Eva Rooij ()
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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
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
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
Reinier A. Boon: Amsterdam University Medical Center VU
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

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20361-3

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