Therapeutic strategy for atherosclerosis targeting for CETP

背景：CETP在胆固醇逆向转运中起重要作用。CETP抑制剂JTT-705对CETP活性的抑制增加血清apo A-I水平并抑制动脉粥样硬化。为了阐明CETP抑制增加HDL水平的机制，我们检查了JTT-705对胆固醇喂养的兔中apo A-I的体内动力学性质的影响。研究方法：随机选择日本白色家兔，以（a）正常兔饲料LRC-4（n=10），（B）含0.2%胆固醇的饲料（n=9），或（c）（B）和0.75% JTT-705的混合物（n=7）喂养7个月。测定CETP活性和血清脂蛋白水平。通过在研究结束时注射放射性碘标记的apo A-I进行体内apo A-I动力学。结果：JTT-705对胆固醇喂养家兔的CETP活性抑制率为38.5%。与正常饲料喂养相比，胆固醇喂养降低SR [8.3 ± 1.1 vs. 10.1 ± 1.8 mg/Kg/d]和血清apo A-1水平，并增加FCR [0.61 ± 0.07 vs. 0.52 ± 0.09 /d]。JTT-705使胆固醇喂养家兔中降低的SR [11.2 ± 2.9 mg/Kg/天]和血清apo A-I水平以及升高的FCR [0.50 ± 0.06 /天]正常化。结论：CETP活性的抑制有利地影响胆固醇喂养的兔中的脂蛋白代谢，这表明CETP抑制可能是动脉粥样硬化的治疗方法。

Background: CETP plays an important role in the reverse cholesterol transport. Inhibition of CETP activity by a CETP inhibitor, JTT-705, increases serum apo A-l levels and inhibits atherosclerosis. To clarify the mechanism by which CETP inhibition increases HDL levels, we examined the effects of JTT-705 on the in vivo kinetics properties of apo A-l in cholesterol-fed rabbits. Methods: Japanese White rabbits were randomly selected to be fed with (a) a normal rabbit chow, LRC-4 (n=10), (b) a diet containing 0.2% cholesterol (n=9), or (c) admixture of (b) and 0.75% JTT-705 (n=7) for 7 mo. CETP activities and serum levels of lipoproteins were measured. In vivo apo A-l kinetics was performed by injecting radioiodinated apo A-l at the end of the study. Results: JTT-705 inhibited 38.5% of the CETP activity in cholesterol-fed rabbits. Cholesterol-feeding decreased SR [8.3 ± 1.1 vs. 10.1 ± 1.8 mg/Kg/day] and serum levels of apo A-l and increased FCR [0.61 ± 0.07 vs. 0.52 ± 0.09 /day] compared with normal chow-feeding. JTT-705 normalized the reduced SR [11.2 ± 2.9 mg/Kg/day] and serum levels of apo A-l and the increased FCR [0.50 ± 0.06 /day] in cholesterol-fed rabbits. Conclusion: Inhibition of CETP activity favorably affects the lipoprotein metabolism in cholesterol-fed rabbits, suggesting that CETP inhibition may be a therapeutic approach for atherosclerosis.