title: Synergistic effect of combined intramyocardial CD34+ cells and VEGF2 gene therapy after MI.
abstract: Previous studies have shown that local angiogenic gene therapy acts, in part, by recruiting endothelial progenitor cells (EPCs) to ischemic tissue. Recent data indicate that patients with the most severe vascular disease may have insufficient or deficient EPCs and the poorest response to angiogenic therapy. Accordingly, we hypothesized that combining human CD34(+) cell implantation with local vascular endothelial growth factor 2 (phVEGF2) gene therapy might overcome these deficiencies. The addition of VEGF2 to EPC cultures resulted in significant and dose-dependent decreases in EPC apoptosis. Phosphorylated Akt (p-Akt) was increased in VEGF2-treated EPCs. In vivo, myocardial infarction (MI) was induced by ligation of the left anterior descending coronary artery in 34 immunodeficient rats. The animals were then randomized to one of four treatment groups: cell therapy alone with human CD34(+) cells; VEGF2 gene therapy alone; combination therapy with CD34(+) cells plus phVEGF2; or CD34(-) cells and 50 microg empty plasmid. Four weeks after MI, animals treated with combination therapy showed improved fractional shortening, increased capillary density, and reduced infarct size compared with the other three groups. Combination therapy was also associated with an increased number of circulating EPCs 1 week after MI. Combined subtherapeutic doses of cell and gene therapy result in a significant therapeutic effect compared to monotherapy. This approach may overcome therapeutic failures (e.g. inability of certain patients to mobilize sufficient EPCs) and may also offer safety advantages by allowing lower dosing strategies.
authors.affiliation: Division of Cardiovascular Research, Caritas St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shintani
authors.forename: Kengo
authors.initials: K
authors.lastname: Kusano
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ii
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwakura
authors.forename: Lindsay
authors.initials: L
authors.lastname: Heyd
authors.forename: Cynthia
authors.initials: C
authors.lastname: Curry
authors.forename: Andrea
authors.initials: A
authors.lastname: Wecker
authors.forename: Mary
authors.initials: M
authors.lastname: Gavin
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
authors.forename: Marianne
authors.initials: M
authors.lastname: Kearney
authors.forename: Marcy
authors.initials: M
authors.lastname: Silver
authors.forename: Tina
authors.initials: T
authors.lastname: Thorne
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis*; D017209:Apoptosis; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000637:transplantation*; D005260:Female; D015316:Genetic Therapy; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000473:pathology; D051381:Rats; D011923:Rats, Nude; D014182:Transplantation, Autologous; D042442:Vascular Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D018952:Antigens, CD34; D042442:Vascular Endothelial Growth Factors