Antiatherogenic effects of newly developed apolipoprotein A-I mimetic peptide/phospholipid complexes against aortic plaque burden in Watanabe-heritable hyperlipidemic rabbits
Antiatherogenic effects of newly developed apolipoprotein A-I mimetic peptide/phospholipid complexes against aortic plaque burden in Watanabe-heritable hyperlipidemic rabbits
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DOI：
10.1016/j.atherosclerosis.2011.05.029
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发表时间：
2011-10-01
期刊：
影响因子：
5.3
通讯作者：
Saku, Keijiro
中科院分区：
文献类型：
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作者：
Iwata, Atsushi;Miura, Shin-ichiro;Saku, Keijiro
本研究分析了新开发的载脂蛋白 A-I (ApoA-I) 模拟肽/磷脂复合物 (ETC-642) 对体内主动脉斑块负荷的抗动脉粥样硬化作用。我们使用人类巨噬细胞通过 ETC-642 分析胆固醇流出。渡边遗传性高脂血症 (WHHL) 兔子被分为 3 组：低剂量 (15 mg/kg) 和高剂量 ETC-642 (50 mg/kg) 以及安慰剂。测试材料每周注射两次，持续 12 周。在第 0 周和第 12 周时通过血管内超声 (IVUS) 评估主动脉斑块负荷。每 4 周通过毛细管等速电泳分析血浆脂质谱。 ETC-642 对胆固醇流出的影响与传统 rHDL 相当。在 WHHL 兔子中，与安慰剂相比，高剂量 ETC-642 抑制了主动脉粥样硬化的进展。高剂量组斑块体积百分比（%PV）在输注前（30.9%）和输注后（28.6%）之间没有变化，而对照组则从27.8%显着增加至37.9%。 ETC-642 通过将更多负电荷修饰的低密度脂蛋白 (LDL) 转化为负电荷较少的 LDL，显着降低了电荷修饰低密度脂蛋白 (LDL)，并通过将小密度 (sd) LDL 转化为大的、有浮力 (lb) 的 LDL，显着降低了电荷修饰低密度脂蛋白 (LDL)。 %PV 的变化与带负电荷的修饰 LDL (r = 0.61，p < 0.01) 和 sdLDL (r = 0.59，p < 0.01) 的变化呈正相关，与带较少负电荷的 LDL (r = -0.43，p < 0.01) 和 lbLDL (r = -0.57，p < 0.01) 的变化呈负相关。总之，ETC-642 诱导的 sdLDL 重塑为大和 lbLDL 以及胆固醇流出的增强可能会阻止主动脉斑块负荷的进展。基于高密度脂蛋白的治疗可能有助于预防斑块体积的进展。 (C) 2011 Elsevier Ireland Ltd. 保留所有权利。
This study analyzed the antiatherogenic effects of newly developed apolipoprotein A-I (ApoA-I) mimetic peptide/phospholipid complexes (ETC-642) against the aortic plaque burden in vivo. We used human macrophage cells to analyze cholesterol efflux by ETC-642. Watanabe-heritable hyperlipidemic (WHHL) rabbits were divided into 3 groups: low-(15 mg/kg) and high-dose ETC-642 (50 mg/kg), and placebo. The test material was injected twice/week for 12 weeks. The aortic plaque burden was assessed by intravascular ultrasound (IVUS) at 0 and 12 weeks. Plasma lipid profiles were analyzed by capillary isotachophoresis every 4 weeks. ETC-642 had an effect on cholesterol efflux comparable to that of conventional rHDL. In WHHL rabbits, high-dose ETC-642 inhibited the progression of aortic atherosclerosis compared to placebo. There was no change in the percentage of plaque volume (%PV) in the high-dose group between before (30.9%) and after infusion (28.6%), whereas there was a significant increase in the control group from 27.8% to 37.9%. ETC-642 significantly reduced charge-modified low-density lipoprotein (LDL) by converting more negative-charged modified LDL to less negative-charged LDL, and reduced small dense (sd) LDL by converting it into large, buoyant (lb) LDL. Changes in the %PV were positively correlated with changes in negative-charged modified LDL (r = 0.61, p < 0.01) and sdLDL (r = 0.59, p < 0.01), and negatively correlated with changes in less negative-charged LDL (r = -0.43, p < 0.01) and lbLDL (r = -0.57, p < 0.01). In conclusion, the ETC-642-induced remodeling of sdLDL to large and lbLDL and the enhancement of cholesterol efflux may prevent progression of the aortic plaque burden. HDL-based therapy may be useful for preventing the progression of plaque volume. (C) 2011 Elsevier Ireland Ltd. All rights reserved.