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      Principles and Applications of Rabbit Models for Atherosclerosis Research

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          Abstract

          Rabbits are one of the most used experimental animals for biomedical research, particularly as a bioreactor for the production of antibodies. However, many unique features of the rabbit have also made it as an excellent species for examining a number of aspects of human diseases such as atherosclerosis. Rabbits are phylogenetically closer to humans than rodents, in addition to their relatively proper size, tame disposition, and ease of use and maintenance in the laboratory facility. Due to their short life spans, short gestation periods, high numbers of progeny, low cost (compared with other large animals) and availability of genomics and proteomics, rabbits usually serve to bridge the gap between smaller rodents (mice and rats) and larger animals, such as dogs, pigs and monkeys, and play an important role in many translational research activities such as pre-clinical testing of drugs and diagnostic methods for patients. The principle of using rabbits rather than other animals as an experimental model is very simple: rabbits should be used for research, such as translational research, that is difficult to accomplish with other species. Recently, rabbit genome sequencing and transcriptomic profiling of atherosclerosis have been successfully completed, which has paved a new way for researchers to use this model in the future. In this review, we provide an overview of the recent progress using rabbits with specific reference to their usefulness for studying human atherosclerosis.

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          Most cited references54

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          Effect of torcetrapib on the progression of coronary atherosclerosis.

          Levels of high-density lipoprotein (HDL) cholesterol are inversely related to cardiovascular risk. Torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, increases HDL cholesterol levels, but the functional effects associated with this mechanism remain uncertain. A total of 1188 patients with coronary disease underwent intravascular ultrasonography. After treatment with atorvastatin to reduce levels of low-density lipoprotein (LDL) cholesterol to less than 100 mg per deciliter (2.59 mmol per liter), patients were randomly assigned to receive either atorvastatin monotherapy or atorvastatin plus 60 mg of torcetrapib daily. After 24 months, disease progression was measured by repeated intravascular ultrasonography in 910 patients (77%). After 24 months, as compared with atorvastatin monotherapy, the effect of torcetrapib-atorvastatin therapy was an approximate 61% relative increase in HDL cholesterol and a 20% relative decrease in LDL cholesterol, reaching a ratio of LDL cholesterol to HDL cholesterol of less than 1.0. Torcetrapib was also associated with an increase in systolic blood pressure of 4.6 mm Hg. The percent atheroma volume (the primary efficacy measure) increased by 0.19% in the atorvastatin-only group and by 0.12% in the torcetrapib-atorvastatin group (P=0.72). A secondary measure, the change in normalized atheroma volume, showed a small favorable effect for torcetrapib (P=0.02), but there was no significant difference in the change in atheroma volume for the most diseased vessel segment. The CETP inhibitor torcetrapib was associated with a substantial increase in HDL cholesterol and decrease in LDL cholesterol. It was also associated with an increase in blood pressure, and there was no significant decrease in the progression of coronary atherosclerosis. The lack of efficacy may be related to the mechanism of action of this drug class or to molecule-specific adverse effects. (ClinicalTrials.gov number, NCT00134173 [ClinicalTrials.gov].). Copyright 2007 Massachusetts Medical Society.
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            Effective gene targeting in rabbits using RNA-guided Cas9 nucleases.

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              Efficient Generation of Myostatin Gene Mutated Rabbit by CRISPR/Cas9

              CRISPR/Cas9 has been widely used in generating site-specific genetically modified animal models. Myostatin (MSTN) is a negative regulator of muscle mass, related to muscle growth and differentiation. The knockout of MSTN with the desired phenotype of double muscle has been successfully generated in mice, goats, pigs and cattle, but not in rabbits. In this study, the MSTN knockout (KO) rabbits were generated by co-injection of Cas9 mRNA and sgRNA into zygotes. The typical phenotype of double muscle with hyperplasia or hypertrophy of muscle fiber was observed in MSTN KO rabbits. Furthermore, a similar phenotype was found in the F1 generation, suggesting that the mutation of MSTN could be stably inherited in the MSTN KO rabbits. In summary, we have successfully generated MSTN KO rabbits using CRISPR/Cas9 system with high efficiency, which is a reliable and effective animal model for the study of muscle development and related diseases.
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                Author and article information

                Journal
                J Atheroscler Thromb
                J. Atheroscler. Thromb
                jat
                jat
                Journal of Atherosclerosis and Thrombosis
                Japan Atherosclerosis Society
                1340-3478
                1880-3873
                1 March 2018
                : 25
                : 3
                : 213-220
                Affiliations
                [1 ]Department of Molecular Pathology, Faculty of Medicine, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan
                [2 ]Department of Pathology, Xi'an Medical University, Xi'an, China
                [3 ]Research Center for Vascular Biology, Yangzhou University School of Medicine, Yangzhou, China
                Author notes
                Address for correspondence: Jingyan Liang, Research Center for Vascular Biology, Yangzhou University School of Medicine, Yangzhou, China E-mail: jyliang@ 123456yzu.edu.cn
                Article
                10.5551/jat.RV17018
                5868506
                29046488
                97648d8f-b206-49b4-8879-4379dc273e4a
                2018 Japan Atherosclerosis Society

                This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License. http://creativecommons.org/licenses/by-nc-sa/3.0/

                History
                : 13 September 2017
                : 18 September 2017
                Page count
                Figures: 1, Tables: 3, References: 65, Pages: 8
                Categories
                Review

                animal models,hypercholesterolemia,atherosclerosis,rabbits,transgenic

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