Reverse D4F, an Apolipoprotein-AI Mimetic Peptide, Inhibits Atherosclerosis in ApoE-null Mice
Reverse D4F, an Apolipoprotein-AI Mimetic Peptide, Inhibits Atherosclerosis in ApoE-null Mice
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DOI：
10.1177/1074248411434598
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发表时间：
2012-09-01
影响因子：
2.6
通讯作者：
Kashyap, Moti L.
中科院分区：
文献类型：
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作者：
Qin, Shucun;Kamanna, Vaijinath S.;Kashyap, Moti L.
目的：合成载脂蛋白-AI的A类两亲性螺旋肽类似物（apoAI;具有不同的苯丙氨酸残基）是正在研究的用于动脉粥样硬化的新兴治疗方法。利用反转录测序，我们设计了反向-D4 F（Rev-D4 F）肽，其具有18个D-氨基酸，含有4个苯丙氨酸残基，并且反向顺序允许侧链残基与亲本L-氨基酸肽的侧链残基精确对齐并且可重叠。本研究探讨了Rev-D4 F对载脂蛋白E（apoE）基因敲除小鼠动脉粥样硬化的影响及其机制。材料/方法：ApoE缺失小鼠喂食普通饲料，并口服饮用水中的水（对照）、Rev-D4 F或L4 F模拟肽（0.4 mg/mL，相当于1.6 mg/d），持续6周。测量主动脉根部粥样硬化病变面积、病变巨噬细胞含量和血浆高密度脂蛋白（HDL）影响单核细胞趋化性的能力。结果如下：Rev-D4 F显著降低apoE基因敲除小鼠主动脉窦粥样硬化病变面积和病变巨噬细胞含量，而不影响血浆总胆固醇和HDL-胆固醇水平。来自Rev-D4 F处理的小鼠的HDL表现出增强的抗炎单核细胞趋化活性，而低密度脂蛋白（LDL）表现出降低的促炎活性。在体外研究中，Rev-D4 F抑制LDL氧化、内皮细胞血管细胞粘附分子1（VCAM-1）和单核细胞趋化因子1（MCP-1）表达以及单核细胞粘附至主动脉内皮细胞。结论：Rev-D4 F通过抑制内皮炎症/氧化事件和改善HDL功能来抑制动脉粥样硬化。这些数据表明，Rev-D4 F可能是一种有效的apoAI模拟肽，用于进一步开发预防动脉粥样硬化。
Objective: Synthetic class A amphipathic helical peptide analogs of apolipoprotein-AI (apoAI; with varied phenylalanine residues) are emerging therapeutic approaches under investigation for atherosclerosis. Utilizing retroinverso sequencing, we designed reverse-D4F (Rev-D4F) peptide with 18 D-amino acids containing 4 phenylalanine residues and reverse order that allows the side chain residues to be of exact alignment and superimposable to those of the parent L-amino acid peptide. This study examined the effect of Rev-D4F on atherosclerosis in apolipoprotein E (apoE)-null mice and the underlying mechanisms. Materials/Methods: ApoE-null mice were fed a chow diet and administered water (control), Rev-D4F, or L4F mimetic peptides (0.4 mg/mL, equivalent to 1.6 mg/d) orally in drinking water for 6 weeks. Aortic root atherosclerotic lesion area, lesion macrophage content, and the ability of plasma high-density lipoprotein (HDL) to influence monocyte chemotaxis were measured. Results: Rev-D4F significantly decreased aortic sinus atherosclerotic lesion area and lesion macrophage content without affecting plasma total and HDL-cholesterol levels in apoE-null mice. The HDL from Rev-D4F-treated mice showed enhanced anti-inflammatory monocyte chemotactic activity, while low-density lipoprotein (LDL) exhibited reduced proinflammatory activity. In in vitro studies, Rev-D4F inhibited LDL oxidation, endothelial cell vascular cell adhesion molecule 1 (VCAM-1), and monocyte chemotactic factor 1 (MCP-1) expression, and monocyte adhesion to aortic endothelial cells. Conclusions: The Rev-D4F inhibits atherosclerosis by inhibiting endothelial inflammatory/oxidative events and improving HDL function. The data suggest that Rev-D4F may be an effective apoAI mimetic peptide for further development in preventing atherosclerosis.