GATA4 regulates Fgf16 to promote heart repair after injury

While the mammalian heart could regenerate during the neonatal stage, such an endogenous regenerative capacity is lost with age. Importantly, replication of cardiomyocytes is found to be the key mechanism responsible for neonatal cardiac regeneration. Unraveling the transcriptional regulatory network for inducing cardiomyocyte replication will, therefore, provide important insights into development of novel therapies to drive cardiac repair after injury. Here, we explored if the key cardiac transcription factor GATA4 is required for neonatal mouse heart regeneration. Using the neonatal mouse heart cryoinjury and apical resection models with an inducible loss of GATA4 specifically in cardiomyocytes, we found severely depressed ventricular function in the Gata4 ablated mice (mutant) after injury. This was accompanied with reduced cardiomyocyte replication. In addition, the mutant hearts displayed impaired coronary angiogenesis and increased hypertrophy and fibrosis after injury. Mechanistically, we found that the paracrine factor FGF16 was significantly reduced in the mutant hearts after injury compared with that of the littermate controls and was directly regulated by GATA4. Cardiac specific overexpression of FGF16 via adeno-associated virus subtype 9 (AAV9) in the mutant hearts partially rescued the cryoinjury-induced cardiac hypertrophy; promoted cardiomyocyte replication and improved heart function after injury. Altogether, our data demonstrated that GATA4 is required for neonatal heart regeneration through regulation of Fgf16, suggesting that paracrine factors could be of potential use in promoting myocardial repair.