通过稳定低密度脂蛋白受体而降低低密度脂蛋白胆固醇,并防止动脉硬化
Jin-Kai Wang1, Yang Li2, Xiao-Lu Zhao1
1Institute for Advanced Studies, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, China (J.-K.W., X.-L.Z., Y.-B.L., J.T., Y.-Y.X., Y. Liu, Y.W., X.-J.S., X.-Y.L., B.-L.S., J.L.).
Circulation
|February 22, 2022
概括
通过降低LDL受体 (LDLR) 来降低LDL胆固醇. 抑制PK会增加LDLR,降低胆固醇,并预防动脉样硬化,从而确定PK作为治疗点.
科学领域:
- 生物化学
- 心血管科学
- 遗传学
背景情况:
- 血中的高胆固醇会加快动脉样硬化, 这是一个长达数十年的无症状过程.
- 动脉硬化斑块破裂导致血栓形成,导致心肌梗塞或中风.
- 降低胆固醇对于预防动脉样硬化心血管疾病至关重要.
研究的目的:
- 确定与低密度脂蛋白受体 (LDLR) 结合的蛋白质.
- 在调节胆固醇水平和动脉样硬化的过程中研究Pekallikrein (PK).
- 评估PK作为心血管疾病的潜在治疗点.
主要方法:
- 通过使用LDLR作为诱,确定PK为LDLR结合蛋白.
- 分析了人体血清PK与脂质水平之间的相关性.
- 在动物模型中利用基因删除和击败PK (大鼠,小鼠,大鼠).
- 评估了PK抑制和抗PK抗体对脂质水平和动脉样硬化的影响.
- 产生了PK和Apolipoprotein的双击小鼠,以研究动脉样硬化的进展.
主要成果:
- 直接与LDLR结合,促进其溶酶体降解.
- 血清PK度与LDL胆固醇水平呈正相关性.
- 在动物中,PK遗传衰竭会增加肝脏的LDLR并降低循环中的胆固醇.
- 包括中和抗体在内的PK抑制通过升高肝脏LDLR来降低血脂质.
- 在小鼠中,PK缺乏会减缓动脉样硬化的进展.
结论:
- 通过诱导LDLR降解来调节循环中的胆固醇.
- 通过PK切除可稳定LDLR,降低LDL胆固醇,并防止动脉样硬化斑块的形成.
- 在治疗动脉样硬化心血管疾病方面,PK是一种有前途的治疗点.
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