title: Improving the efficacy of therapeutic angiogenesis by UTMD-mediated Ang-1 gene delivery to the infarcted myocardium.
abstract: This study aimed to verify the feasibility and efficacy of ultrasound-targeted microbubble destruction (UTMD)-mediated angiopoietin-1 (Ang-1) gene delivery into the infarcted myocardium. Microbubbles carrying anti-intercellular adhesion molecule-1 (ICAM-1) antibody were prepared and identified. The microbubbles carrying anti-ICAM-1 antibody selectively adhered to the interleukin (IL)-1β-stimulated ECV304 cells and to the ischemic vascular endothelium, and the infarct area was examined to evaluate the targeting ability of ICAM-1 microbubbles in vitro and in vivo. The intravenous administration of the Ang-1 gene was carried out by UTMD in rabbits with acute myocardial infarction (AMI). The rabbits were divided into the control (no treatment), non-targeted microbubble destruction (non-TMB) and the ICAM-1 TMB (TMB) group. Gene delivery by direct intramyocardial injection (IMI) served as a reference. Two weeks later, regional myocardial perfusion and cardiac function were evaluated by echocardiography, and Ang-1 gene-mediated angiogenesis was assessed histologically and biochemically. The results revealed that the ICAM-1-targeted microbubbles selectively adhered to the IL-1β-stimulated ECV304 cells in vitro and to the ischemic vascular endothelium in the infarct area of the rabbits with AMI. Two weeks after the delivery of the Ang-1 gene, compared with the non-TMB group, left ventricular function and myocardial perfusion at the infarct area had improved in the TMB and IMI group (p<0.01). Ang-1 gene expression was detectable in the non-TMB, TMB and IMI group, while its expression was higher in the latter 2 groups (all p<0.01). The microvascular density (MVD) of the infarct area in the non-TMB, TMB and IMI group was 65.6 ± 4.4, 96.7 ± 2.1 and 100.7 ± 3.6, respectively (p<0.01). The findings of our study indicate that UTMD-mediated gene delivery may be used to successfully deliver the Ang-1 gene to the infarcted myocardium, thus improving the efficacy of therapeutic angiogenesis. This may provide a novel strategy for future gene therapy.
authors.affiliation: Department of Ultrasound Imaging, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Deng
authors.affiliation: Department of Ultrasound Imaging, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of Ultrasound Imaging, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Cao
authors.affiliation: Department of Ultrasound Imaging, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
authors.forename: Hong-Ning
authors.initials: HN
authors.lastname: Song
authors.affiliation: Department of Ultrasound Imaging, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
authors.forename: Jin-Ling
authors.initials: JL
authors.lastname: Chen
authors.affiliation: Department of Ultrasound Imaging, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
mesh_terms: D042683:Angiopoietin-1 / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D003326:Coronary Circulation; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D008297:Male; D045423:Microbubbles; D009203:Myocardial Infarction / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D018919:Neovascularization, Physiologic; D010957:Plasmids / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D011817:Rabbits; D014162:Transfection / Q000379:methods*; D014465:Ultrasonics
chemical_list: D042683:Angiopoietin-1; D018799:Intercellular Adhesion Molecule-1