Abstract 429: Rosiglitazone Reduces Development and Rupture of Experimental Aortic Aneurysms
Several case-control studies have shown a negative correlation between diabetes and aortic aneurysm. Using an animal model of aneurysm, and cell cultures, we investigated the effects of Rosiglitazone (RGZ), a drug used in the treatment of type II diabetes. Twenty-eight 12 month old ApoE-deficient mice were randomised to three groups. All animals had an osmotic pump inserted subcutaneously on the flank, the positive control group and treatment group released Angiotensin-II (Ang-II) (1μg/min/kg), the sham operated group released saline. The treatment group received RGZ (10mg/kg/day) in their drinking water one week before inserting the pumps and continuously during the following 28 day release of Ang-II. Plasma was collected to measure the lipid profile and determine concentration of IL-6 and active MMP-2 and MMP-9. Gross pathology was evaluated using video micrometry. Expression of proteins and RNAs were analysed using immunohistochemistry, ELISA and quantitative real time RT-PCR. The effect of RGZ on Ang-II induced DNA-binding of transcription factor Egr-1 was determined using electrophoretic mobility shift assays of human aortic smooth muscle cell cultures. In comparison to the positive control group of animals, treatment with Rosiglitazone inhibited the occurrence of fatal rupture (5/10 vs 0/10) and reduced maximal dilatation of the aorta (5.6 ± 0.26 vs 2.6 ± 0.4 mm2). RGZ reduced the concentration of total cholesterol but no significant difference in the atherosclerotic burden was found between groups. RGZ inhibited the angiotensin II-induced tissue expression of AT1a receptor, but had no affect on increased mRNA expression of AT2 receptor, MMP-2 or MMP-9. Plasma protein concentrations of IL6, and MMP-9 were increased by Ang-II and decreased by RGZ. The amount of collagen deposited in the supra-renal region of the abdominal aortae was increased in animals treated with RGZ. RGZ inhibited Ang-II induced DNA binding of the transcription factor, early growth response-1 (Egr-1) in human smooth muscle cells. These data suggest that RGZ reduces the incidence of development and rupture in this murine model of aneurysm through AT1a mediated effects on transcriptional regulation of genes which determine phenotypic status of the vessel wall.