Administration of a novel reprogramming formula improves cardiac function and decreases cardiac fibrosis in a...

The reprogramming of fibroblasts into (induced) cardiomyocytes offers a direct myocardial regeneration strategy for improving postinfarction myocardial function. Compared to lower-order species, human cells are relatively resistant to such reprogramming. We previously found that p63-transactivation inhibitory domain (TID; the portion of p63 that physical interacts and interferes with its activation of the epigenetic repressor HDAC1) combined with the cardio-differentiation factors Hand2 and Myocardin (HM) enhanced rat and human cell transdifferentiation. The present study sought to determine the in vivo effects of this reprogramming strategy in a rat myocardial infarction model.

Adult male and female rats underwent left anterior descending coronary artery ligation, followed 3 weeks later by direct myocardial injection of adenovectors encoding vascular endothelial growth factor (VEGF)+TID/HM, VEGF+GATA4+MEF2C+TBX5 (GMT), or green fluorescent protein (GFP) (n = 12/group). After serial echocardiography over a 4-week period, the animals were euthanized, and histologic analysis was performed.

Animals treated with VEGF+GMT or VEGF+TID/HM demonstrated an increase in ejection fraction (EF) of 8% ± 17% and 7% ± 15%, respectively, at 4 weeks after vector administration, while EF decreased by 3% ± 7% in GFP-treated animals (P < .05). Systolic left ventricular posterior wall thickness also was increased in the treated groups but decreased in the control group (P < .05). Fibrosis likewise was reduced in treated animals compared with those receiving GFP (P < .01).

Adenoviral mediated administration of VEGF+TID/HM to the rat heart induced improvements in cardiac function and decreased fibrosis after myocardial infarction equivalent to that observed with VEGF+GMT administration. Given the efficacy of VEGF+TID/HM versus VEGF+GMT in cardio-differentiating human cells, these findings suggest the use of VEGF+TID/HM as a potential human myocardial regeneration strategy.