title: Complementary therapeutic effects of dual delivery of insulin-like growth factor-1 and vascular endothelial growth factor by gelatin microspheres in experimental heart failure.
abstract: OBJECTIVE
  Strategies to prevent adverse left ventricular (LV) remodelling after myocardial infarction have included several traditional approaches and novel cell-based or gene therapies. Delivery of growth factors in post-infarction heart failure has emerged as a valuable alternative strategy. Our aim was to investigate the effects of sequential release of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) from biodegradable gelatin microspheres in experimental heart failure.
  
  
  RESULTS
  Gelatin hydrogel microspheres were known to guarantee a sustained release of encapsulated growth factors, characterized by an initial burst followed by a slower release. Rats with moderate myocardial infarction were randomized to receive empty microspheres (MI), microspheres loaded with IGF-1 or VEGF, or a combination thereof (DUAL). Myocardial injections of microspheres were performed at the time of surgery, and treatment lasted 4 weeks. Echocardiography, LV catheterization, morphometric histology and immunohistochemistry, and molecular assessment of downstream mediators [e.g. Akt, endothelial nitric oxide synthase (eNOS), and sarco/endoplasmic reticulum calcium ATPase-2 (SERCA-2)] were assessed at the end of the treatment period. Infarct sizes were 33 ± 2, 28 ± 4, 24 ± 3, and 16 ± 3% in the MI, IGF-1, VEGF, and DUAL groups, respectively. IGF-1 attenuated LV remodelling, improved LV systolic and diastolic function, increased myocyte size, and reduced apoptotic deaths, capillary loss, and indexes of inflammation. VEGF-treated animals displayed a marked myocardial neoangiogenesis that led to the formation of mature vessels if combined with IGF-1 delivery. Downstream effects of IGF-1 were principally mediated by the Akt-mTOR (mammalian target of rapamycin)-dependent pathway, and both growth factors, particularly VEGF, induced a robust and sustained increase of eNOS.
  
  
  CONCLUSIONS
  IGF-1 and VEGF exerted complementary therapeutic effects in post-infarction heart failure. Biodegradable gelatin microspheres provide sustained and controlled growth factor release locally, exposing myocardial tissue without the side effects of systemic administration.
authors: Department of Internal Medicine and Cardiovascular Sciences, University Federico II, Via Sergio Pansini 5, Naples, Italy. antonio.cittadini@unina.it
authors: Antonio
authors: A
authors: Cittadini
authors: Maria Gaia
authors: MG
authors: Monti
authors: Valentina
authors: V
authors: Petrillo
authors: Giovanni
authors: G
authors: Esposito
authors: Giorgia
authors: G
authors: Imparato
authors: Alessia
authors: A
authors: Luciani
authors: Francesco
authors: F
authors: Urciuolo
authors: Emanuele
authors: E
authors: Bobbio
authors: Carlo F
authors: CF
authors: Natale
authors: Luigi
authors: L
authors: Saccà
authors: Paolo A
authors: PA
authors: Netti
mesh_terms: D020341:Absorbable Implants; D000818:Animals; D006328:Cardiac Catheterization; D004195:Disease Models, Animal; D004337:Drug Carriers; D016503:Drug Delivery Systems; D004359:Drug Therapy, Combination; D004452:Echocardiography; D004562:Electrocardiography; D005500:Follow-Up Studies; D005780:Gelatin; D007150:Immunohistochemistry; D007267:Injections; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage*; D008297:Male; D008863:Microspheres; D009203:Myocardial Infarction / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D009206:Myocardium; D051381:Rats; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage*; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D004337:Drug Carriers; D042461:Vascular Endothelial Growth Factor A; D007334:Insulin-Like Growth Factor I; D005780:Gelatin