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

• Published in: Nature communications Vol. 12; no. 1; p. 84
• Main Authors: Gladka, Monika M., Kohela, Arwa, Molenaar, Bas, Versteeg, Danielle, Kooijman, Lieneke, Monshouwer-Kloots, Jantine, Kremer, Veerle, Vos, Harmjan R., Huibers, Manon M. H., Haigh, Jody J., Huylebroeck, Danny, Boon, Reinier A., Giacca, Mauro, van Rooij, Eva
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.01.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 101/58; 13; 13/95; 38; 38/91; 42; 42/41; 45; 45/77; 59; 692/4019/592/16; 692/4019/592/75/2/1674; 82/51; Angiogenesis; Animals; Cardiomyocytes; Cell adhesion & migration; Cell migration; Cell Movement - genetics; Cell Proliferation - genetics; Crosstalk; Dependovirus - metabolism; Endothelial cells; Gene Expression Regulation; Heart attacks; Homeobox; Humanities and Social Sciences; Humans; Injury prevention; Ischemia; Ischemia - genetics; Ischemia - pathology; Mice; Mice, Knockout; Models, Biological; multidisciplinary; Muscle contraction; Myocardial infarction; Myocardial Infarction - genetics; Myocardial Infarction - pathology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Neovascularization, Physiologic - genetics; Paracrine signalling; Protein Precursors - genetics; Protein Precursors - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Thymosin - analogs & derivatives; Thymosin - genetics; Thymosin - metabolism; Transcription factors; Zinc Finger E-box Binding Homeobox 2 - genetics; Zinc Finger E-box Binding Homeobox 2 - metabolism; Zinc finger proteins
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20361-3

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. ZEB2 transcription factor is increased in a subset of cardiomyocytes during stress to induce cardioprotective effects after injury. Here the authors show that therapeutic delivery of ZEB2 prevents cardiac dysfunction after ischemic damage and promotes the activation of pro-angiogenic signals.