# Hyperlipidemic Rabbit Models for Anti-Atherosclerotic Drug Development
## 3 Hyperlipidemic Rabbit Models for the Development of Drugs
### HDL, Apo A-I, Apo A-I\({}_{Milano}\), and Apo A-I Mimetic Peptides  
HDL, especially its compositional protein apo A-I, possesses a number of physiological functions to protect against atherosclerosis, including reverse cholesterol transport, anti-inflammation, anti-oxidization, mediation of vascular tone, and anti-thrombosis [102; 103; 104]. The concept of elevation of plasma HDL or apo A-I to reduce cardiovascular risk has been suggested by both clinical and experimental studies. Many of these experiments were performed in hypercholesterolemia rabbits, using either HDL or apo A-I (including apo A-I variants and apo A-I mimetic peptides), as summarized in Table 5.  
[PERSON] et al. first examined the effect of HDL administration in cholesterol-fed rabbits. A plasma HDL-VHDL (d = 1.063-1.21 g/mL and d = 1.21-1.25 g/mL) fraction was isolated from normal rabbits. HDL-VHDL was administrated intravenously to 0.5% cholesterol-fed rabbits for eight weeks. HDL-VHDL treatment led to a 61% reduction in aortic atherosclerosis over the control [105]. [PERSON] et al. also demonstrated that such treatment can result in the regression of aortic atherosclerosis (48% reduction) [106]. Most recently, [PERSON] et al. compared the atheoprotective properties of HDLs isolated from normolipidemic and hyperlipidemic rabbits. Atherosclerosis was induced by a combination of cholesterol diet feeding and balloon injury. Administration of HDL from normolipidemic rabbits regressed aortic lesions by 4.3% compared with the baseline, whereas HDL from hyperlipidemia increased the lesions by 6.5% [107]. Direct injection of apo A-I into rabbits to test the atheoprotective effects has been attempted. For example, [PERSON] et al. showed that injection with purified rabbit apo A-I significantly reduced atherosclerosis by 48% over the control rabbits [108]. [PERSON] et al. generated carotid atherosclerosis by an extra-arterial collar placement in 1% cholesterol-fed rabbits, and administration of the apo A-I\({}_{Milano}\)-phosphatidylcholine (PC) complex inhibited neointimal formation without affecting plasma TC levels [109]. [PERSON] et al. evaluated whether apo A-I\({}_{Milano}\) mobilizes lipids from carotid artery fatty streaks. Lipid-rich plaques were generated at common carotid arteries by a perivascular electrical injury, followed by 1.5% cholesterol diet for 90 days. The effect of apo A-I\({}_{Milano}\)-phospholipid complex administration was assessed by intravascular ultrasound. A single administration of the apo A-I\({}_{Milano}\)-phospholipid complex decreased the plaque area (29% reduction with 1000 mg dose) by the end of the 90-min infusion compared with the pre-infusion [110]. [PERSON] et al. reported a plaque regression effect of apo A-I\({}_{Milano}\) using MRI. Abdominal aortic atherosclerosis was induced by a combination of nine-month 0.2% cholesterol-rich diet and twice aortic balloon injury. After lesions were established, recombinant apo A-I\({}_{Milano}\)-phospholipid was administered for four days. Apo A-I\({}_{Milano}\)-phospholipid administration reduced the lesions by 6.1% over the vehicle control and 5.1% compared with baseline [111]. In addition, transgenic expression of human apo A-I and apo A-II also protects against diet-induced atherosclerosis [112; 113].