title: Post-translational regulation of a hypoxia-responsive VEGF plasmid for the treatment of myocardial ischemia.
abstract: Vascular endothelial growth factor (VEGF) gene therapy to promote therapeutic angiogenesis has been advanced as an alternative treatment for myocardial ischemia. The unregulated expression of VEGF and the use of viral vectors, however, have slowed the clinical development of angiogenic gene therapy. The development of clinically beneficial angiogenic gene therapy requires a disease-specific gene expression system and an efficient non-viral gene carrier. To address these requirements, we developed a new post-translationally regulated hypoxia-responsible VEGF plasmid, pβ-SP-ODD-VEGF, and a dendrimer-type bio-reducible polymer, PAM-ABP. The efficacy of VEGF gene therapy with the PAM-ABP/pβ-SP-ODD-VEGF was evaluated and compared to the RTP-VEGF plasmid, a previously constructed hypoxia-inducible plasmid, in an ischemia/reperfusion (I/R) rat model. Cine magnetic resonance imaging was used to analyze the ischemia/reperfusion rats treated with either the PAM-ABP/pβ-SP-ODD-VEGF or the PAM-ABP/RTP-VEGF. The PAM-ABP/pβ-SP-ODD-VEGF treatment more effectively protected cardiomyocytes against apoptosis, preserved left ventricular (LV) function, and prevented LV remodeling compared to the PAM-ABP/RTP-VEGF-treated rats. These results suggest that the pβ-SP-ODD-VEGF with PAM-ABP may be efficacious in the treatment of acute ischemic heart disease.
authors.affiliation: Center for Controlled Chemical Delivery (CCCD), Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112-5820, USA.
authors.forename: Young-Wook
authors.initials: YW
authors.lastname: Won
authors.forename: Arlo N
authors.initials: AN
authors.lastname: McGinn
authors.forename: Minhyung
authors.initials: M
authors.lastname: Lee
authors.forename: Kihoon
authors.initials: K
authors.lastname: Nam
authors.forename: David A
authors.initials: DA
authors.lastname: Bull
authors.forename: Sung Wan
authors.initials: SW
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis; D001120:Arginine / Q000737:chemistry*; D002460:Cell Line; D050091:Dendrimers / Q000737:chemistry*; D015870:Gene Expression; D015316:Genetic Therapy; D060588:LIM Domain Proteins / Q000032:analysis / Q000235:genetics; D008297:Male; D017202:Myocardial Ischemia / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D011073:Polyamines / Q000737:chemistry*; D021382:Protein Sorting Signals; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000235:genetics*
chemical_list: C544610:Crip2 protein, rat; D050091:Dendrimers; D060588:LIM Domain Proteins; C104700:PAMAM Starburst; D011073:Polyamines; D021382:Protein Sorting Signals; D042461:Vascular Endothelial Growth Factor A; C534803:arginine-grafted bioreducible poly(disulfide amine)polymer; D001120:Arginine