In Vivo Cardiac Cellular Reprogramming Efficacy Is Enhanced by Angiogenic Preconditioning of the Infarcted Myocardium With Vascular Endothelial Growth Factor

Background In situ cellular reprogramming offers the possibility of regenerating functional cardiomyocytes directly from scar fibroblasts, obviating the challenges of cell implantation. We hypothesized that pretreating scar with gene transfer of the angiogenic vascular endothelial growth factor (VEG...

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Bibliographic Details
Published in:Journal of the American Heart Association 2012-12, Vol.1 (6), p.e005652-n/a
Main Authors: Mathison, Megumi, P. Gersch, Robert, Nasser, Ahmed, Lilo, Sarit, Korman, Mallory, Fourman, Mitchell, Hackett, Neil, Shroyer, Kenneth, Yang, Jianchang, Ma, Yupo, Crystal, Ronald G., Rosengart, Todd K.
Format: Article
Language:English
Subjects:
angiogenesis
Animals
Drug Therapy, Combination
Echocardiography
Fibrosis - prevention & control
Fluorescent Antibody Technique
GATA4 Transcription Factor - administration & dosage
gene therapy
Gene Transfer Techniques
MEF2 Transcription Factors
myocardial infarction
Myocardial Infarction - drug therapy
Myocardial Infarction - physiopathology
Myocytes, Cardiac - physiology
Myogenic Regulatory Factors - administration & dosage
Neovascularization, Physiologic - drug effects
Neovascularization, Physiologic - physiology
Original Research
Rats
Rats, Inbred F344
stem cells
T-Box Domain Proteins - administration & dosage
Transcription Factors - administration & dosage
Transfection
Treatment Outcome
Vascular Endothelial Growth Factor A - administration & dosage
Ventricular Function - drug effects
Ventricular Function - physiology
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Summary:Background In situ cellular reprogramming offers the possibility of regenerating functional cardiomyocytes directly from scar fibroblasts, obviating the challenges of cell implantation. We hypothesized that pretreating scar with gene transfer of the angiogenic vascular endothelial growth factor (VEGF) would enhance the efficacy of this strategy. Methods and Results Gata4, Mef2c, and Tbx5 (GMT) administration via lentiviral transduction was demonstrated to transdifferentiate rat fibroblasts into (induced) cardiomyocytes in vitro by cardiomyocyte marker studies. Fisher 344 rats underwent coronary ligation and intramyocardial administration of an adenovirus encoding all 3 major isoforms of VEGF (AdVEGF‐All6A+) or an AdNull control vector (n=12/group). Lentivirus encoding GMT or a GFP control was administered to each animal 3 weeks later, followed by histologic and echocardiographic analyses. GMT administration reduced the extent of fibrosis by half compared with GFP controls (12±2% vs 24±3%, P
ISSN:2047-9980
2047-9980
DOI:10.1161/JAHA.112.005652