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(Circulation Research. 2007;100:1626.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Effect of Cell-Based Intercellular Delivery of Transcription Factor GATA4 on Ischemic Cardiomyopathy

Jing Bian, Zoran B. Popovi, Carlos Benejam, Matthew Kiedrowski, L. Leonardo Rodriguez, Marc S. Penn

From the Departments of Cell Biology (J.B., M.K., M.S.P.), Biomedical Engineering (M.S.P.), and Cardiovascular Medicine (Z.B.P., C.B., L.L.R., M.S.P.), Cleveland Clinic Foundation; and Department of Chemical and Biomedical Engineering (J.B., M.S.P.), Cleveland State University, Ohio.

Correspondence to Marc S. Penn, MD, PhD, Director, Bakken Heart-Brain Institute, Departments of Cardiovascular Medicine and Cell Biology, NE3, 9500 Euclid Ave, Cleveland, OH 44195. E-mail pennm{at}ccf.org

Recent loss-of-function studies highlight the importance of the transcription factor GATA4 in the myocardial response to injury in the adult heart. However, the potential effects of gain-in-function of GATA4 overexpression, and transcription factors in general, is hindered by the fact that transcription factors are neither secreted nor taken up by cells. Chimeric proteins incorporating motifs of cell-penetrating proteins are secreted from cells and internalized by surrounding cells. We engineered a chimeric protein consisting of GATA4 and the cell-penetrating protein VP22. Cardiac fibroblasts stably transfected with the GATA4:VP22, GFP:VP22, or green fluorescent protein (GFP) constructs were transplanted into Lewis rats 1 month after left anterior descending ligation. GATA4:VP22 expression in the border zone was associated with increased cardiac myosin expression and cardiac myocyte size (30 µm versus 19 µm, P<0.01). Compared with the GFP:VP22 control group, 6 weeks after cardiac fibroblast transplantation (10 weeks after myocardial infarction), animals that received GATA4:VP22-expressing cardiac fibroblasts demonstrated increased cardiac function and less negative remodeling. These data demonstrate a novel strategy for transcription factor delivery to injured myocardium and indicate that the delivery of GATA4 locally to the infarct border zone induces multiple local effects in the border zone cardiac myocytes resulting in beneficial ventricular remodeling and improved global left ventricular function.

Key Words: GATA4 • myocardial infarct • cell-based gene therapy • VP22 • intercellular delivery of protein

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Cell-Based GATA4 Cardiac Gene Transfer Using Cell-Penetrating Peptide

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