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: To develop a method for induction of atherosclerosis without germline genetic engineering.
Methods and Results: Recombinant adeno-associated viral vectors (rAAV) were engineered to encode gain-of-function proprotein convertase subtilisin/kexin type 9 (PCSK9) mutants, and mice were given a single intravenous vector injection followed by high-fat diet feeding. Plasma PCSK9 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 non-murine species was demonstrated by inducing hypercholesterolemia and early atherosclerosis in Golden Syrian hamsters.
Conclusions: Single injections of PCSK9-encoding rAAV vectors is a rapid and versatile method to induce atherosclerosis in animals. This method should prove useful for experiments that are high-throughput or involves genetic techniques, strains, or species that do not combine well with current genetically engineered models.
- Received October 27, 2013.
- Revision received March 26, 2014.
- Accepted March 27, 2014.