title: Pathogenetic role of hypercholesterolemia in a novel preclinical model of vascular injury in pigs.
abstract: OBJECTIVE
  Most strategies against intimal hyperplasia developed in several preclinical models failed in terms of clinical application, often due to a discrepancy between animal and human disease. The aim of this study was to setup for the first time a porcine vascular injury model with mild hypercholesterolemia able to significantly increase the degree of stenosis resembling human settings and investigate the pathogenetic role of hypercholesterolemia on protective genes and inflammatory response affecting matrix deposition and cell proliferation.
  
  
  METHODS
  Pigs were fed with standard (SD, n=7) or high-cholesterol diet (HCD, n=7) for 120 days. A balloon angioplasty injury was induced in carotid arteries.
  
  
  RESULTS
  Hypercholesterolemia induced a mild significant increase of total and LDL cholesterolemia. HCD significantly increased the degree of stenosis (48+/-3% vs. 13+/-4%, p=0.001), with induction of cell proliferation, matrix deposition, TGF-beta1/TGFbetaRII and MMP2 expression and reduction of collagen. The reduced expression of the protective gene heme oxygenase-1 and inducible-nitric oxide synthase in HCD was associated to a systemic inflammation with a significant increase in circulating leukocytes, serum IFN-gamma and TNF-alpha and a local inflammatory response with an increase of CD3-positive cell infiltrates. There was a significant correlation between CD3 infiltrates and the degree of stenosis.
  
  
  CONCLUSIONS
  We developed for the first time a porcine vascular injury model with mild hypercholesterolemia able to significantly increase the degree of stenosis and showed the pathogenetic role of hypercholesterolemia on intimal hyperplasia. New therapeutical strategies to prevent restenosis can be tested in this preclinical hypercholesterolemic model resembling human disease.
authors.affiliation: Department of Surgical Sciences, University of Milano-Bicocca, Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Busnelli
authors.forename: Alberto
authors.initials: A
authors.lastname: Froio
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Bacci
authors.forename: Massimo
authors.initials: M
authors.lastname: Giunti
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cerrito
authors.forename: Roberto
authors.initials: R
authors.lastname: Giovannoni
authors.forename: Monica
authors.initials: M
authors.lastname: Forni
authors.forename: Fabio
authors.initials: F
authors.lastname: Gentilini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Scagliarini
authors.forename: Gaetano
authors.initials: G
authors.lastname: Deleo
authors.forename: Cristian
authors.initials: C
authors.lastname: Benatti
authors.forename: Biagio Eugenio
authors.initials: BE
authors.lastname: Leone
authors.forename: Giorgio Maria
authors.initials: GM
authors.lastname: Biasi
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Lavitrano
mesh_terms: D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D016893:Carotid Stenosis / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D008078:Cholesterol, LDL / Q000097:blood; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006937:Hypercholesterolemia / Q000150:complications* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006965:Hyperplasia; D018836:Inflammation Mediators / Q000097:blood; D007371:Interferon-gamma / Q000097:blood; D007962:Leukocytes / Q000276:immunology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D012720:Severity of Illness Index; D013552:Swine; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D017252:CD3 Complex; D008078:Cholesterol, LDL; D024042:Collagen Type I; D018836:Inflammation Mediators; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D020778:Matrix Metalloproteinase 2