Abstract 456: Hypercholesterolemia Induced by a PCSK9 Gain-of-function Mutation Augments AngII-induced AAAs in C57BL/6 Mice
Objective: Angiotensin II (AngII)-induced abdominal aortic aneurysms (AAAs) have increased incidence in hyper- versus normocholesterolemic mice. The purpose of this study was to determine whether infection of C57BL/6 mice with an adeno-associated viral vector (AAV) expressing a gain-of-function mutation of mouse proprotein convertase subtilisin/kexin type 9 (PCSK9) to induce hypercholesterolemia would augment AngII-induced AAAs.
Methods and Results: Male C57BL/6 mice (8 weeks old; The Jackson Laboratory) were assigned randomly to groups infected with AAVs containing either an empty vector or a mouse PCSK9 gain-of-function (D374Y) mutation. Mice received a single intraperitoneal injection of AAV (n=10/group at a dosage of 10 x 1010 genomic copies/mouse) and were fed a saturated fat-enriched diet for 6 weeks. Two weeks after AAV injection, mice were infused with AngII (1,000 ng/kg/min) for 28 days. Plasma PCSK9 concentrations were increased profoundly 2 weeks after injection of AAVs containing the PCSK9 mutation and remained elevated during the study (P<0.001). Expression of the PCSK9 mutant significantly increased plasma total cholesterol concentrations to greater than 800 mg/dl within 2 weeks that were maintained through 4 weeks of AngII infusion. Increased plasma cholesterol concentrations were due to increased VLDL and LDL cholesterol, as determined by size exclusion chromatography. In agreement with high plasma cholesterol concentrations, atherosclerotic lesion area of the aortic arch region was increased profoundly by the PCSK9 mutant (P<0.001). AAAs were quantified by ex vivo maximal aortic width of the suprarenal aorta. There was a significant increase of maximal aortic width of abdominal aortas (P=0.005) in AngII-infused mice expressing the PCSK9 mutant.
Conclusion: AAV-mediated expression of a PCSK9 gain-of-function mutation is a rapid, easy, and efficient approach to induce hypercholesterolemia and promote AngII-induced AAAs in C57BL/6 mice.
Author Disclosures: A. Balakrishnan: None. D.A. Howatt: None. L.A. Cassis: None. A. Daugherty: None. H. Lu: None.
- © 2015 by American Heart Association, Inc.