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, Eva van Rooij

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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.

Original languageEnglish
Pages (from-to)84
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 04 Jan 2021

Keywords

  • Animals
  • Cell Movement/genetics
  • Cell Proliferation/genetics
  • Dependovirus/metabolism
  • Gene Expression Regulation
  • Humans
  • Ischemia/genetics
  • Mice, Knockout
  • Models, Biological
  • Myocardial Infarction/genetics
  • Myocytes, Cardiac/metabolism
  • Neovascularization, Physiologic/genetics
  • Protein Precursors/genetics
  • RNA, Messenger/genetics
  • Thymosin/analogs & derivatives
  • Zinc Finger E-box Binding Homeobox 2/genetics

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