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Post-translational regulated and hypoxia-responsible VEGF plasmid for efficient secretion

Title
Post-translational regulated and hypoxia-responsible VEGF plasmid for efficient secretion
Author
이민형
Keywords
Gene therapy; Hypoxia; VEGF; Myocardial ischemia
Issue Date
2012-06
Publisher
Elsevier Science B.V., Amsterdam.
Citation
Journal of controlled release,Vol.160 No.3 [2012],p525-531
Abstract
Gene therapy using angiogenic genes has emerged as a potentially viable alternative treatment strategy for myocardial ischemia. Non-specific expression of angiogenic genes, however, may result in side effects, including the growth of occult tumors. Regulation of gene expression may help to avoid the occurrence of these side effects. In this study, a plasmid expressing vascular endothelial growth factor (VEGF) was constructed with an oxygen dependent degradation (ODD) domain and a secretion signal peptide (SP) in order to stabilize the VEGF protein and facilitate the secretion of VEGF protein, specifically under hypoxic conditions. We found that this plasmid, p beta-SP-ODD-VEGF, expresses the SP-ODD-VEGF protein at increased levels under hypoxic conditions compared to normoxic conditions. Since the size of the ODD domain is almost the same as that of VEGF, the ODD-VEGF fusion protein may have lower secretion efficiency. To address this issue, a furin recognition site was located between the ODD domain and the VEGF site to facilitate elimination of the SP-ODD domain from the fusion protein before its secretion. This optimizes the likelihood that the VEGF secreted from the target cells will be wild-type VEGF. Treatment with a furin inhibitor reduced the secretion efficiency of the VEGF, indicating that furin digestion increases the secretion of VEGF. The secreted wild-type VEGF facilitated the growth of endothelial cells more efficiently under hypoxic conditions than normoxic conditions. These results suggest that this plasmid, p beta-SP-ODD-VEGF, warrants further study as a more efficient form of hypoxia-inducible gene therapy for the treatment of myocardial ischemia. (C) 2012 Elsevier B.V. All rights reserved. GENE DELIVERY
URI
https://www.sciencedirect.com/science/article/pii/S0168365912001964?via%3Dihubhttp://hdl.handle.net/20.500.11754/39310
ISSN
0168-3659
DOI
10.1016/j.jconrel.2012.03.010
Appears in Collections:
COLLEGE OF ENGINEERING[S](공과대학) > BIOENGINEERING(생명공학과) > Articles
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