Abstract 293: ApoB-Containing Lipoproteins Contribute to Augmentation of AngII-Induced Abdominal Aortic Aneurysms

Abstract

Background and objective: Presence of abdominal aortic aneurysms (AAA) is associated with dyslipidemia in humans. Hypercholesterolemic mice having a predominance of ApoB-containing lipoproteins are more susceptible to Angiotensin (Ang)II-induced AAA formation. A recent publication demonstrated that exogenously delivered high-density lipoprotein (HDL) prevented AngII-induced AAAs. ApoAI is the major apolipoprotein of HDL. The purpose of this study was to determine whether manipulations of ApoAI or ApoB-containing lipoproteins influence the development of AngII-induced AAA. Methods and Results: Eight week old male ApoAI +/+ or -/- mice with either wild type or LDL receptor -/- background were fed normal diet and infused with AngII (1 mg/kg/min) for 28 days. Plasma lipoprotein distributions were resolved by size exclusion gel chromatography. Deficiency of ApoAI led to profound reductions of plasma HDL-C concentrations in both strains. However, ApoAI deficiency did not exacerbate AngII-induced AAA as determined by maximal outer widths of suprarenal aortas (ApoAI +/+ versus -/-:1.52 ± 0.25 versus 1.22 ± 0.18 mm, P= 0.2 for C57BL/6 strain;1.21 ± 0.18 versus 1.11 ± 0.17 mm, P= 0.2 for LDLR -/- strain). Ezetimibe, an intestinal cholesterol absorption inhibitor, was administered to eight week old male ApoE -/- mice fed normal diet. Ezetimibe decreased plasma cholesterol concentrations from 451 ± 8 to 204 ± 18 mg/dl (P<0.001). This reduction was due to reductions in ApoB-containing lipoproteins. Administration of ezetimibe decreased AngII-induced AAA (control versus ezetimibe: 2.25 ± 0.28 mm versus 1.37 ± 0.1 mm, P=0.009). The same dose of ezetimibe was also administered to ApoE -/- mice fed western diet. Plasma cholesterol concentrations were reduced (from 980 ± 86 to 546 ± 11 mg/dl, P<0.001) attributed to reductions of apoB-containing lipoproteins. Administration of ezetimibe led to a profound reduction of atherosclerosis in western diet fed apoE -/- mice, but did not attenuate AngII-induced AAAs. Conclusion: ApoB-containing lipoproteins, rather than HDL, contribute to the augmentation of AngII-induced AAAs. However, substantial reductions in apoB-containing lipoproteins were required to attenuate AngII-induced AAA.