Genetically Modified Rabbits for Cardiovascular Research

Abstract

Rabbits are one of the most used experimental animals for investigating the mechanisms of human cardiovascular disease and lipid metabolism because they are phylogenetically closer to human than rodents (mice and rats). Cholesterol-fed wild-type rabbits were first used to study human atherosclerosis more than 100 years ago and are still playing an important role in cardiovascular research. Furthermore, transgenic rabbits generated by pronuclear microinjection provided another means to investigate many gene functions associated with human disease. Because of the lack of both rabbit embryonic stem cells and the genome information, for a long time, it has been a dream for scientists to obtain knockout rabbits generated by homologous recombination-based genomic manipulation as in mice. This obstacle has greatly hampered using genetically modified rabbits to disclose the molecular mechanisms of many human diseases. The advent of genome editing technologies has dramatically extended the applications of experimental animals including rabbits. In this review, we will update genetically modified rabbits, including transgenic, knock-out, and knock-in rabbits during the past decades regarding their use in cardiovascular research and point out the perspectives in future.

The High-Level Expression Analysis of RhPA In The RhPA/gGH Double-Transgenic Rabbits And Its Thrombolysis Activity In Vitro

“…Forty rabbits were successfully delivered. Sixteen rhPA/gGH double transgenic rabbits (10♂,6♀) were obtained by PCR integration detection, and the double gene integration rate reached 40.0%, which was consistent with the integration efficiency of transgenic rabbits reported at home and abroad [16,[38][39][40][41] . The mammary gland expression levels of the six rhPA/gGH double transgenic female rabbits showed that rhPA expressed level in whey were about 4.98-12.24g/L, which were much higher than those of rhPA single transgenic rabbits (0.27-0.63 g/L), and increased by about 17.2-23.8 times.…”

Atherosclerosis: Known and unknown

“…Due to their short life spans, short gestation period, high number of progeny, relatively low cost (compared with other large animals such as dogs, pigs and monkeys), and availability of genomics and proteomics, 56 rabbits can bridge the gap between smaller rodents and larger animals, and play an important role in translational research such as pre-clinical testing of drugs and diagnostic methods for patients. 52,57,58 Lipoprotein metabolism features of rabbits are close to those of humans, as are the lesions of atherosclerosis, being advantages to examine lipoprotein metabolism and atherosclerosis (Table 1). We created both transgenic and KO rabbits to study apolipoproteins (apo), including apo(a), apoAII, apoB, apoCIII, apoE, enzymes (endothelial lipase, hepatic lipase and lipoprotein lipase) and cholesteryl ester transfer protein proteins (CETP) expressed in the liver.…”

“…We created both transgenic and KO rabbits to study apolipoproteins (apo), including apo(a), apoAII, apoB, apoCIII, apoE, enzymes (endothelial lipase, hepatic lipase and lipoprotein lipase) and cholesteryl ester transfer protein proteins (CETP) expressed in the liver. 58 We also generated different rabbit models to examine the functional roles F I G U R E 6 Simplified schema of initial cellular events during the pathogenesis of atherosclerosis. Risk factors, such as hypercholesterolemia (yellow dots), may upregulate the adhesion molecules of endothelial cells (EC), which leads to the adherence of monocytes (Mon) and T lymphocytes (Lym) on the surface of intima (left).…”

Harnessing the Potential of CRISPR/Cas in Atherosclerosis: Disease Modeling and Therapeutic Applications

“…Interestingly, genetic ablation of CETP gene in the rabbit model demonstrated athero-protective effects, suggesting a potential therapeutic target for atherosclerosis treatment [146]. Meanwhile, the Watanabe heritable hyperlipidemic (WHHL) rabbits are often used as a human familial hypercholesterolemic model due to its characteristic high LDL levels [147]. Following the discovery of CRISPR/Cas9, knockout rabbit models are made possible with the capability to target different gene of interests [148].…”