载脂蛋白 A1的模拟肽4F 可通过氧化高密度脂蛋白改善功能抗动脉粥样硬化
撰文 黄炜
严重冠状动脉粥样硬化(AS)引起的冠心病是目前全球发病率和死亡率最高的疾病之一。高密度脂蛋白(HDL) 是目前公认的血管保护因子,然而多项大型临床实验结果显示:胆固醇酯转移蛋白(CETP)抑制剂虽然显著提高 HDL 水平,却不能降低心血管事件的发生率。前期研究表明,氧化高密度脂蛋白(ox-HDL)使内皮损伤后的修复能力降低,导致 HDL 的保护作用降低。因此,改善ox-HDL 功能具有重要的临床意义。载脂蛋白 A1的模拟肽4F 已被证明在多种动物模型中有血管保护作用,但其保护作用的具体机制尚不清楚,这种保护作用是否与修复HDL的血管保护功能有关仍待进一步研究明确。
2017年4月26日,国际学术期刊 Redox Biology 杂志在线发表了北京大学医学部教授郑乐民研究组最新研究成果(论文信息见文末)。他们发现模拟肽4F显著促进脐静脉内皮细胞的增殖、迁移和伪足形成,一氧化氮的产生,降低内皮细胞中活性氧的产生,同时恢复氧化高密度脂蛋白的功能紊乱,此过程受B类Ⅰ型清道夫受体(SR-B1)的调控,同时可激活Akt、 ERK 和 eNOS 使其磷酸化水平升高,而siRNA 敲除 SR-B1 和 eNOS 后,4F的保护作用显著降低。动物实验证明4F可以促进正常小鼠颈动脉电损伤后血管的再内皮化,降低血浆中 lysoPC 与尿液中异前列烷的含量,而对SR-B1敲除小鼠的损伤后血管内皮无明显保护作用。
该研究提示模拟肽4F 可以促进血管内皮修复,同时可使氧化高密度脂蛋白引起的再内皮化功能障碍得到逆转,为动脉粥样硬化的治疗提供新的思路。同时,模拟肽4F作为一种稳定的肽类具有很高的成药价值。研究生贺丹和赵明明为论文第一作者,郑乐民教授和潘兵副教授为论文通讯作者。
标题 Apolipoprotein A-1 mimetic peptide 4F promotes endothelial repairing and compromises reendothelialization impaired by oxidized HDL through SR-B1
期刊 Redox Biology
作者 Dan Hea, Mingming Zhaoa, Congying Wub, Wenjing Zhangc, Chenguang Niua, Baoqi Yua, Jingru Jinc, Liang Jia, Belinda Willardd, Anna V. Mathewe, Y. Eugene Chene, Subramaniam Pennathure, Huiyong Yinf, Yuan Heg, Bing Pana, Lemin Zhenga
发表日期 Online 8 December 2017
摘要 Disruption of endothelial monolayer integrity is the primary instigating factor for many cardiovascular diseases. High density lipoprotein (HDL) oxidized by heme enzyme myeloperoxidase (MPO) is dysfunctional in promoting endothelial repair. Apolipoprotein A-1 mimetic 4 F with its pleiotropic benefits has been proven effective in many in vivo models. In this study we investigated whether 4 F promotes endothelial repair and restores the impaired function of oxidized HDL (Cl/NO2-HDL) in promoting re-endothelialization. We demonstrate that 4 F and Cl/NO2-HDL act on scavenger receptor type I (SR-B1) using human aorta endothelial cells (HAEC) and SR-B1 (-/-) mouse aortic endothelial cells. Wound healing, transwell migration, lamellipodia formation and single cell migration assay experiments show that 4 F treatment is associated with a recovery of endothelial cell migration and associated with significantly increased endothelial nitric oxide synthase (eNOS) activity, Akt phosphorylation and SR-B1 expression. 4 F increases NO generation and diminishes oxidative stress. In vivo, 4 F can stimulate cell proliferation and re-endothelialization in the carotid artery after treatment with Cl/NO2-HDL in a carotid artery electric injury model but fails to do so in SR-B1(-/-) mice. These findings demonstrate that 4 F promotes endothelial cell migration and has a potential therapeutic benefit against early endothelial injury in cardiovascular diseases.
链接:
https://www.sciencedirect.com/science/article/pii/S221323171730722X
联系客服