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Am J Physiol Heart Circ Physiol 284: H1429-H1440, 2003. First published December 27, 2002; doi:10.1152/ajpheart.00885.2002
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Vol. 284, Issue 4, H1429-H1440, April 2003

Gene therapy vector-mediated expression of insulin-like growth factors protects cardiomyocytes from apoptosis and enhances neovascularization

E. J. Su1, C. L. Cioffi2, S. Stefansson1, N. Mittereder1, M. Garay2, D. Hreniuk2, and G. Liau1

1 Genetic Therapy Incorporated, Gaithersburg, Maryland 20878; and 2 Metabolic and Cardiovascular Diseases Therapeutic Area, Novartis, Summit, New Jersey 07901

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 ~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.

vascular endothelial growth factor; adenoviral vector; human endothelial cells; growth factor; Matrigel


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