Engineered Zinc Finger–Activating Vascular Endothelial Growth Factor Transcription Factor Plasmid DNA Induces Therapeutic Angiogenesis in Rabbits With Hindlimb Ischemia

Autor: Edward J. Rebar, Pascal J. Goldschmidt-Clermont, Chunming Dong, S. Kaye Spratt, Bruce Klitzman, Christopher D. Kontos, Casey C. Case, Brian H. Johnstone, Qunsheng Dai, Keith L. March, Jianhua Huang, Brian H. Annex, Joseph Rokovich
Rok vydání: 2004
Předmět:
Vascular Endothelial Growth Factor A
Endothelium
Angiogenesis
medicine.medical_treatment
Genetic Vectors
DNA
Recombinant
Ischemia
Cytomegalovirus
Neovascularization
Physiologic
Apoptosis
Simian virus 40
Protein Engineering
Injections
Intramuscular
Andrology
chemistry.chemical_compound
Physiology (medical)
Genes
Synthetic
medicine
Animals
Protein Isoforms
RNA
Messenger
Therapeutic angiogenesis
Antigens
Viral
Tumor
Promoter Regions
Genetic
Binding Sites
business.industry
Growth factor
NF-kappa B
Transcription Factor RelA
Zinc Fingers
DNA
Genetic Therapy
medicine.disease
Capillaries
Hindlimb
Femoral Artery
Vascular endothelial growth factor
Vascular endothelial growth factor A
medicine.anatomical_structure
Gene Expression Regulation
chemistry
Immunology
Female
Rabbits
Cardiology and Cardiovascular Medicine
business
Blood vessel
Zdroj: Circulation. 110:2467-2475
ISSN: 1524-4539
0009-7322
DOI: 10.1161/01.cir.0000145139.53840.49
Popis: Background— Therapeutic angiogenesis seeks to promote blood vessel growth to improve tissue perfusion. Vascular endothelial growth factor (VEGF) exists in multiple isoforms. We investigated an engineered zinc finger–containing transcription factor plasmid designed to activate the endogenous VEGF gene (ZFP-VEGF). Methods and Results— New Zealand White rabbits (n=56) underwent unilateral femoral artery ligation and excision. At day 10 postoperatively, the ischemic muscle received ZFP treatment (500 μg ZFP-VEGF plasmid) or no ZFP treatment (β-galactosidase, empty, or no plasmid). Group 1 (n=13) was harvested 3 days after injection to examine VEGF mRNA by real-time polymerase chain reaction and protein by ELISA. Groups 2 (n=13) and 3 (n=10) were harvested 11 days after injection. Group 2 was studied by histology and group 3, by histology and changes in blood flow. Groups 4 and 5 (n=10 each) were harvested 22 and 32 days after injection, respectively, and studied for changes in blood flow. In group 1, VEGF mRNA copy numbers were significantly higher for VEGF 121 , VEGF 165 , VEGF 189 , and protein in the ZFP-VEGF-treatment versus no-ZFP-treatment arms. In groups 2 and 3, capillary density and proliferating cells were significantly greater and apoptosis significantly lower in the treatment versus no-treatment arms. Changes in the blood flow ratio of the ischemic to the nonischemic limb were significantly greater in the treatment versus no-ZFP-treatment groups (6.57±1.52% versus 3.38±0.87%, P P P Conclusions— This engineered ZFP-VEGF–activating transcription factor may provide a novel approach to treat peripheral arterial disease.
Databáze: OpenAIRE
Externí odkaz: