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

Danielle Versteeg,Jantine Monshouwer-Kloots,Arwa Kohela,Harmjan R Vos,Bas Molenaar,Eva Van Rooij,Monika M Gladka,Manon M H Huibers,Reinier A Boon,Veerle Kremer,Mauro Giacca,Danny Huylebroeck,Lieneke Kooijman,Jody J Haigh

doi:10.1038/s41467-020-20361-3

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.

Highlights

The disruption in blood supply due to myocardial infarction is a critical determinant for infarct size and subsequent deterioration in function
K-medoids clustering of 1-Pearson correlation showed that based on gene expression similarities, these cells could be clustered in 14 different cell populations (Fig. 1c and Supplementary Fig. 1a)
Discovery of players involved in myocardial repair after ischemia could serve in the development of enhanced therapeutic interventions

Summary

Introduction

The disruption in blood supply due to myocardial infarction is a critical determinant for infarct size and subsequent deterioration in function. 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. We show by gain- and loss-of-function studies that ZEB2 confers cardioprotective effects after ischemia via an increase in circulating levels of TMSB4 and PTMA7–9 In line with these findings, the therapeutic delivery of ZEB2 to cardiomyocytes is able to recapitulate these protective effects after MI. These data suggest that the increase of ZEB2 in cardiomyocytes in response to stress protects the heart from ischemic damage via cell non-autonomous effects, which may hold great promise for future heart failure therapies

Methods

Results

Conclusion