Effect of cell-based intercellular delivery of transcription factor GATA4 on ischemic cardiomyopathy.
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 mum versus 19 mum, 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.
Bian
Jing
J
Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, OH, USA.
Popovic
Zoran B
ZB
Benejam
Carlos
C
Kiedrowski
Matthew
M
Rodriguez
L Leonardo
LL
Penn
Marc S
MS
D000818:Animals; D048429:Cell Size; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism* / Q000637:transplantation; D050991:GATA4 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D009203:Myocardial Infarction / Q000628:therapy*; D017202:Myocardial Ischemia / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics*; D014162:Transfection; D016277:Ventricular Function, Left / Q000235:genetics; D015678:Viral Structural Proteins / Q000235:genetics
D050991:GATA4 Transcription Factor; D011993:Recombinant Fusion Proteins; D015678:Viral Structural Proteins; C073413:herpes simplex virus type 1 protein VP22; D049452:Green Fluorescent Proteins