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具有功能的增益的PCSK9 D374Y突变通过抑制PPARα表达来加剧动脉样硬化

Yuan Feng Cui^1,2, Xiao Cui Chen^1,2, Tuoluonayi Mijiti^1,2

¹Xinjiang Key Laboratory of Cardiovascular Disease Research, State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, Xinjiang, China.

Scientific reports

|February 26, 2025

概括

功能增强PCSK9 (PCSK9DY) 在缺乏PPARα的小鼠中恶化了动脉样硬化,增加了脂质和炎症. 在PCSK9^DY的小鼠中,过度表达PPARα减少了动脉样硬化,突出了PPARα.

科学领域:

心血管生物学心血管生物学
代谢性疾病研究研究
分子医学是分子医学.

背景情况:

蛋白转化酶亚提利辛/凯辛9型 (PCSK9) 是降低脂质和治疗动脉样硬化 (AS) 的治疗标.
过氧体增殖器激活受体α (PPARα) 调节脂质代谢和炎症,但其与AS中PCSK9的相互作用尚不清楚.

研究的目的:

调查PCSK9 (PCSK9^DY) 功能的增加对PPARα淘汰小鼠动脉样硬化的影响.
探索PPARα过度表达在PCSK9驱动动动脉硬化中的治疗潜力.

主要方法:

将PCSK9^DY转化为PPARα淘汰赛小鼠和人类PCSK9转基因小鼠.
对血脂水平的酶分析和对大动脉斑块和炎症的组织学分析.
使用小鼠初级腹巨细胞 (MPM) 进行体外研究,以评估泡细胞形成和炎症性细胞因子分泌.

主要成果:

PCSK9^DY表达加剧了高胆固醇血症,增加了大动脉斑块面积,并在PPARα淘汰赛小鼠中促进了炎症透.
重组hPCSK9蛋白通过SR-A和TLR4/NF-κB通路增加了PPARα淘汰MPM中的泡细胞形成和炎症性细胞因子分泌.
在人类PCSK9^DY转基因小鼠中,AAV8.2-PPARα基因治疗降低了血脂水平并减弱了AS.

结论:

在没有PPARα的情况下,PCSK9^DY通过增加血脂和炎症来加速AS的进展.
PPARα对PCSK9-介导动脉样硬化有保护作用,其过度表达是AS的潜在治疗策略.

关键词:

动脉样硬化是一种动脉样硬化.炎症炎症是一种炎症.脂蛋白质是一种脂蛋白质.过氧体增殖器激活受体α.蛋白转化酶亚提利辛/凯类型9 血清蛋白酶.

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