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抑制PCSK9通过减少通过LDLR/STAT-3/ROR-γt通路的Th17细胞分化来改善实验性自身免疫心肌炎

Miao Yu¹, Wenjing Tang¹, Wei Liang¹

¹Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

International immunopharmacology

|September 30, 2023

概括

在实验性自身免疫性心肌炎中,蛋白转化酶 (subtilisin kexin type 9) (PCSK9) 抑制减少了心脏炎症. 阻断PCSK9降低了Th17细胞分化,这表明PCSK9是心肌炎的治疗点.

科学领域:

免疫学免疫学免疫学
心血管研究研究心血管研究
分子生物学分子生物学

背景情况:

众所周知,蛋白转化酶子素素9型 (PCSK9) 有关胆固醇的调节作用.
新兴证据将PCSK9与超出脂质代谢的炎症和自身免疫性疾病联系起来.
在心肌炎中PCSK9的作用仍然在很大程度上未被探索.

研究的目的:

研究PCSK9在实验性自身免疫性心肌炎 (EAM) 中的作用和潜在机制.
评估PCSK9抑制在改善心肌炎中的治疗潜力.

主要方法:

使用MyHC-α免疫建立了一个EAM小鼠模型.
在EAM小鼠中使用PCSK9抑制剂 (evolocumab).
评估心脏炎症,PCSK9水平,免疫细胞群 (CD4 +,CD8 + T 细胞,巨细胞) 和心肌细胞参与.
对CD4+T细胞进行了体外研究,以阐明PCSK9通过LDLR/STAT3/ROR-γt通路对Th17分化的机制.

主要成果:

在EAM小鼠中,PCSK9抑制显著降低了心脏炎症.
在抑制后观察到心脏和外周血液PCSK9水平降低.
PCSK9在心脏CD4+ T细胞,CD8+ T细胞,巨细胞和心肌细胞中表达.
抑制PCSK9通过降低ROR-γt的调节,特别减少了Th17细胞的分化,而不会影响Th1,Th2或Treg细胞.
在体外,PCSK9被证明可以直接促进Th17细胞分化.

结论:

抑制PCSK9可以改善实验性自身免疫性心肌炎的严重程度.
治疗效果是由通过LDLR/STAT3/ROR-γt通路减少Th17细胞分化的介导.
PCSK9代表了治疗心肌炎的有前途的治疗标.

关键词:

进化中的黄肌心炎是一种心肌炎.蛋白转化酶子素素9型 (PCSK9) 是一种 Th17细胞分化的过程

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