Pathogenetic role of hypercholesterolemia in a novel preclinical model of vascular injury in pigs.
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.
Busnelli
Marco
M
Department of Surgical Sciences, University of Milano-Bicocca, Milano, Italy.
Froio
Alberto
A
Bacci
Maria Laura
ML
Giunti
Massimo
M
Cerrito
Maria Grazia
MG
Giovannoni
Roberto
R
Forni
Monica
M
Gentilini
Fabio
F
Scagliarini
Alessandra
A
Deleo
Gaetano
G
Benatti
Cristian
C
Leone
Biagio Eugenio
BE
Biasi
Giorgio Maria
GM
Lavitrano
Marialuisa
M
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
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