新規再プログラミング製剤の投与による心筋梗塞モデルにおける心機能の改善と心臓線維化の低減

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.