Publication Date
12-1-2025
Journal
JTCVS Open
DOI
10.1016/j.xjon.2025.09.019
PMID
41473092
PMCID
PMC12745098
PubMedCentral® Posted Date
9-20-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Background: 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.
Methods: 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.
Results: 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).
Conclusions: 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.
Keywords
myocardial regeneration, myocardial infarction, gene therapy, induced cardiomyocytes, cell transdifferentiation, cardio-differentiation
Published Open-Access
yes
Recommended Citation
Mathison, Megumi; Pathan, Saliha S; Lackan, Aliya; et al., "Administration of a Novel Reprogramming Formula Improves Cardiac Function and Decreases Cardiac Fibrosis in a Myocardial Infarction Model" (2025). Faculty, Staff and Students Publications. 6124.
https://digitalcommons.library.tmc.edu/baylor_docs/6124