Apolipoprotein E deficient rats generated via zinc-finger nucleases exhibit pronounced in-stent restenosis

Abstract

The long-term success of coronary stent implantation is limited by in-stent restenosis (ISR). In spite of a broad variety of animal models available, an ideal high-throughput model of ISR has been lacking. Apolipoprotein E (apoE) deficient rats enable the evaluation of human-sized coronary stents while at the same time providing an atherogenic phenotype. Whereas apoE deficient rats have been proposed as animal model of atherosclerosis, to date it is unknown whether they also develop pronounced ISR. We sought to assess ISR after abdominal aorta stent implantation in apoE deficient rats. A total of 42 rats (16 wildtype, 13 homozygous apoE^−/− and 13 heterozygous apoE^+/− rats) underwent abdominal aorta stent implantation. After 28 days blood samples were analyzed to characterize lipid profiles. ISR was assessed by histomorphometric means. Homozygous apoE^−/− rats exhibited significantly higher total cholesterol and low-density cholesterol levels than wildtype apoE^+/+ and heterozygous apoE^+/− rats. ISR was significantly pronounced in homozygous apoE^−/− rats as compared to wildtype apoE^+/+ (p = <0.0001) and heterozygous apoE^+/− rats (p = 0.0102) on western diet. Abdominal aorta stenting of apoE^−/− rats is a reliable model to investigate ISR after stent implantation and thus can be used for the evaluation of novel stent concepts. Apolipoprotein E (apoE) deficient rats have been proposed as animal model of atherosclerosis. We investigated the development of restenosis 28 days after stent implantation into the abdominal aorta of wildtype apoE^+/+, homozygous apoE^−/− and heterozygous apoE^+/− rats, respectively. Homozygous apoE^−/− rats exhibited significantly higher LDL and significantly lower HDL cholesterol levels compared to wildtype apoE^+/+ and heterozygous apoE^+/− rats. Restenosis after stent implantation was significantly pronounced in western-diet-fed homozygous apoE^−/− rats, accompanied by a significantly increased neointimal thickness. Thus, apoE knockout rats exhibit elevated restenosis and might provide a novel tool for testing of innovative stent concepts.