Gene therapy vector-mediated expression of insulin-like growth factors protects cardiomyocytes from apoptosis and enhances neovascularization.
IGF-I and IGF-II are single-chain polypeptide growth factors that regulate pleiotropic cellular responses. We have characterized the effect of recombinant IGF proteins, as well as third-generation adenoviral vectors encoding either IGF-I or IGF-II genes, on cardiomyocyte apoptosis and on angiogenesis. We found that endothelial cells cultured in the presence of the extracellular protein laminin exhibit a robust response to IGF-I and -II proteins via enhanced cell migration and angiogenic outgrowth. Furthermore, IGF vectors greatly enhanced neovascularization in an in vivo Matrigel model. Transduction of cardiomyocytes with the IGF adenoviral vectors resulted in a dose- and time-dependent increase in the expression of IGF-I or IGF-II protein. This correlated with abrogation of apoptosis induced by ischemia-reoxygenation, ceramide, or heat shock with optimal inhibition of approximately 80%. We conclude that gene transfer of IGF-I and IGF-II is a plausible strategy for the local delivery of IGFs to treat ischemic heart disease and heart failure by stimulating angiogenesis and protecting cardiomyocytes from cell death.
Su
E J
EJ
Genetic Therapy Incorporated, Gaithersburg, Maryland 20878, USA.
Cioffi
C L
CL
Stefansson
S
S
Mittereder
N
N
Garay
M
M
Hreniuk
D
D
Liau
G
G
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001011:Aorta; D017209:Apoptosis; D002448:Cell Adhesion; D002633:Chemotaxis; D004730:Endothelium, Vascular / Q000166:cytology; D016222:Fibroblast Growth Factor 2; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D006321:Heart / Q000196:embryology; D006331:Heart Diseases / Q000628:therapy; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D007797:Laminin / Q000378:metabolism; D017202:Myocardial Ischemia / Q000628:therapy; D009206:Myocardium / Q000166:cytology*; D018919:Neovascularization, Physiologic; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014471:Umbilical Veins
D007797:Laminin; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II