Abstract 101: Characteristics of Angiotensin II-induced Abdominal Aortic Aneurysms in Selected Mouse Strains Expressing PCSK9D377Y

Abstract

Objective: Our previously study demonstrated that infection of C57BL/6 mice with an adeno-associated viral vector (AAV) expressing the proprotein convertase subtilisin/kexin type 9 (PSCK)9D377Y gain-of-function mutant led to augmentation of angiotensin II (AngII)-induced abdominal aortic aneurysms (AAAs). The purpose of this study was to optimize PCSK9D377Y expression in mice for AngII-induced AAA formation. We also determined the susceptibility of PCSK9D377Y expression to increase AngII-induced AAA in selected normolipidemic mouse strains. Methods and Results: To determine optimal dose for infection, C57BL/6 mice were injected intraperitoneally with AAVs containing either an empty vector or PCSK9 D377Y at three doses (3 x 10 10 , 10 x 10 10 , or 30 x 10 10 genomic copies/mouse). Mice were fed a Western diet for 6 weeks starting immediately after AAV injections. Two weeks after AAV injection, mice were infused with AngII (1,000 ng/kg/min) for 4 weeks. Plasma PCSK9 concentrations were increased dose-dependently in mice injected with AAV containing PCSK9D377Y mutation, accompanied by increased plasma cholesterol concentrations. Infection with the intermediate and high doses of PCSK9D377Y.AAV led to equivalent increases of maximal width of abdominal aortas. Therefore, the intermediate dose was used in the following experiments. Effects of PCSK9 D377Y.AAV infection was then determined in 5 normolipidemic mouse strains (C57BL/6, 129, FVB, DBA/2, and BALB/c). C57BL/6 mice were the most susceptible to AAV infection, whereas BALB/c mice were completely resistant. Consistently, C57BL/6 mice with increased plasma cholesterol concentrations had higher AngII-induced AAA formation. PCSK9D377Y.AAV infected male C57BL/6 mice were also compared with age-matched male LDL receptor -/- mice fed the same Western diet. Although plasma total cholesterol concentrations were lower in mice infected with PCSK9D377Y.AAV than LDL receptor -/- mice, these two mouse strains had equivalent AAA formation. Conclusions: This study provided evidence that C57BL/6 mouse strain was the most susceptible strain to AAV-driven expression of a gain of function mutant of PCSK9 that promoted AngII-induced AAAs to an equivalent incidence as LDL receptor -/- mice.