Induction of Atherosclerosis in Mice and Hamsters Without Germline Genetic Engineering

RATIONALE:Atherosclerosis can be achieved in animals by germline genetic engineering, leading to hypercholesterolemia, but such models are constrained to few species and strains, and they are difficult to combine with other powerful techniques involving genetic manipulation or variation. OBJECTIVE:T...

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Published in:Circulation research 2014-05, Vol.114 (11), p.1684-1689
Main Authors: Bjørklund, Martin Mæng, Hollensen, Anne Kruse, Hagensen, Mette Kallestrup, Dagnæs-Hansen, Frederik, Christoffersen, Christina, Mikkelsen, Jacob Giehm, Bentzon, Jacob Fog
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
Animals
Aorta - pathology
Apolipoproteins E - deficiency
Apolipoproteins E - genetics
Atherosclerosis - genetics
Atherosclerosis - pathology
Cricetinae
Disease Models, Animal
Female
Gene Transfer Techniques
Genetic Engineering
Genetic Vectors - genetics
Germ-Line Mutation
Mesocricetus
Mice
Mice, Inbred C57BL
Mice, Knockout
Proprotein Convertase 9
Proprotein Convertases - genetics
Receptors, LDL - deficiency
Receptors, LDL - genetics
Serine Endopeptidases - genetics
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Summary:RATIONALE:Atherosclerosis can be achieved in animals by germline genetic engineering, leading to hypercholesterolemia, but such models are constrained to few species and strains, and they are difficult to combine with other powerful techniques involving genetic manipulation or variation. OBJECTIVE:To develop a method for induction of atherosclerosis without germline genetic engineering. METHODS AND RESULTS:Recombinant adeno-associated viral vectors were engineered to encode gain-of-function proprotein convertase subtilisin/kexin type 9 mutants, and mice were given a single intravenous vector injection followed by high-fat diet feeding. Plasma proprotein convertase subtilisin/kexin type 9 and total cholesterol increased rapidly and were maintained at high levels, and after 12 weeks, mice had atherosclerotic lesions in the aorta. Histology of the aortic root showed progression of lesions to the fibroatheromatous stage. To demonstrate the applicability of this method for rapid analysis of the atherosclerosis susceptibility of a mouse strain and for providing temporal control over disease induction, we demonstrated the accelerated atherosclerosis of mature diabetic Akita mice. Furthermore, the versatility of this approach for creating atherosclerosis models also in nonmurine species was demonstrated by inducing hypercholesterolemia and early atherosclerosis in Golden Syrian hamsters. CONCLUSIONS:Single injections of proprotein convertase subtilisin/kexin type 9–encoding recombinant adeno-associated viral vectors are a rapid and versatile method to induce atherosclerosis in animals. This method should prove useful for experiments that are high-throughput or involve genetic techniques, strains, or species that do not combine well with current genetically engineered models.
ISSN:0009-7330
1524-4571
DOI:10.1161/CIRCRESAHA.114.302937