Mild-hypercholesterolemia exacerbates intimal hyperplasia after vascular injury by suppressing heme oxygenase-1 expression

Intimal hyperplasia (IH) limits the success of many vascular interventions, including bypass grafting endarterectomy and stenting. IH following vascular injury is characterized by vascular smooth muscle cells proliferation and migration, matrix deposition, inflammation. The aim of the study was to investigate, in a mild-hypercholesterolemic pig model of vascular injury: i) the role of Heme Oxygenase-1 (HO-1) in the pathogenesis of IH; ii) the molecular mechanism of prevention and therapy mediated by atorvastatin; iii) the atorvastatin-mediated induction of HO-1 in response to vascular injury. Balloon injury (BI) was used to induce IH in pig carotid arteries. Pigs were divided in 3 groups (n=7 each): standard diet; high-cholesterol diet; high-cholesterol diet and atorvastatin (80 mg/die). Carotid sections were analyzed by morphometric and immunohistochemical analyses. Hemochrome, cholesterolemia, proinflammatory cytokines profiles were also evaluated. Hypercholesterolemia induced a significant increase of total and LDL-cholesterol, exacerbated IH, increased extracellular matrix deposition, inhibited HO-1 expression and increased the local and systemic inflammatory state compared to standard diet. Atorvastatin prevented IH development by enhancing HO-1 expression, reducing the number of T-cell infiltrating the site of vascular injury, and lowering the plasmatic concentration of proinflammatory cytokines. In conclusion: i) a high-cholesterol diet induces a persistent state of vascular inflammation that worsen the vascular response following BI; ii) atorvastatin has a protective role in the pathogenesis and outcome of inflammatory response following vascular injury; iii) atorvastatin prevents IH inducing HO-1 expression in the vascular wall.