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.

Conclusion: 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.