TY - JOUR
T1 - Cardiomyocytes stimulate angiogenesis after ischemic injury in a ZEB2-dependent manner
AU - Gladka, Monika M.
AU - Kohela, Arwa
AU - Molenaar, Bas
AU - Versteeg, Danielle
AU - Kooijman, Lieneke
AU - Monshouwer-Kloots, Jantine
AU - Kremer, Veerle
AU - Vos, Harmjan R.
AU - Huibers, Manon M. H.
AU - Haigh, Jody J.
AU - Huylebroeck, Danny
AU - Boon, Reinier A.
AU - Giacca, Mauro
AU - van Rooij, Eva
N1 - Funding Information: This work was supported by the Leducq Foundation (14CVD04; to E.v.R.), the European Research Council under the European Union’s Seventh Framework Programme (ERC Grant Agreement CoG 615708 MICARUS; to E.v.R.) and Belspo IAPVII-07 Devrepair (to D.H. and J.J.H.). D.H. was further supported by Fund for Scientiffic Research-Flanders (FWO, G.0A31.16). M.M.G. was funded by a Dr. Dekker postdoctoral fellowship from the Dutch Heart Foundation (NHS2016T009). H.R.V. was supported by the Proteins@Work initiative of The Netherlands Organization for Scientific Research (NWO) with the grant number: 184.032.201. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1/12
Y1 - 2021/1/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85098634029&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-020-20361-3
DO - https://doi.org/10.1038/s41467-020-20361-3
M3 - Article
C2 - 33398012
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 84
ER -