Impact of the cardiomyocyte transcription factor GATA4 for cardiac regeneration
Final Report Abstract
Taken together, we demonstrate here that cardiac abundance of the transcription factor GATA4 was high at P1, but became strongly reduced at P7 in parallel with the loss of regenerative capacity. Reconstitution of cardiac GATA4 levels by adenoviral gene-transfer markedly improved cardiac regeneration after cryoinjury at P7. In contrast, the myocardial scar was larger in cardiomyocyte specific GATA4 knock-out (CM-G4-KO) mice after cryoinjury at P0, indicative of impaired regeneration, which was accompanied by reduced cardiomyocyte proliferation and reduced myocardial angiogenesis in CM-G4-KO mice. Cardiomyocyte proliferation was also diminished in cardiac explants from CM-G4-KO mice and in isolated cardiomyocytes with reduced GATA4 expression. The lack of endogenous GATA4 also ablated the regenerative response to neonatal pressure overload, indicating that GATA4 acts as a nodal regulator of neonatal regeneration that could help to regenerate the heart after different forms of injuries. Mechanistically, decreased GATA4 levels caused the downregulation of several proregenerative genes (among them interleukin-13, Il13) in the myocardium. Interestingly, systemic administration of IL-13 rescued defective heart regeneration in CM-G4-KO mice after cryoinjury and could be evaluated as therapeutic strategy in the future. Cell type specific RNA-sequencing that we are currently performing could help to identify more pro-regenerative candidate gene that could similarly be evaluated as regenerative therapeutic approach.
Publications
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The transcription factor GATA4 promotes myocardial regeneration in neonatal mice. EMBO Molecular Medicine. 2017; 9: 265-279
Malek Mohammadi M, Kattih B, Grund A, Froese N, Korf-Klingebiel M, Gigina A, Schrameck U, Rudat C, Liang Q, Kispert A, Wollert KC, Bauersachs J and Heineke J
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Induction of cardiomyocyte proliferation and angiogenesis protects neonatal mice from pressure overload-associated maladaptation. JCI Insight. 2019 Jul 23; 5
Malek Mohammadi M, Abouissa A, Isyatul A, Xie Y, Cordero J, Shirvani A, Gigina A, Engelhardt M, Trogisch FA, Geffers R, Dobreva G, Bauersachs J and Heineke J
