阻断Sigmar1会加剧甲基胺诱导的高血压
Zhen-Zhen Xu1, Jie Zhou1, Ke Duan1
1Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou 510515, PR China.
概括
长期暴露于甲基胺会通过促进血管纤维化引起高血压. 西格玛1受体 (Sigmar1) 起着关键作用,向它可能为甲基胺诱导的高血压提供新的治疗方法.
科学领域:
- 心血管药理学心血管药理学
- 血管生物学 血管生物学
- 药物诱导的疾病 药物诱导的疾病
背景情况:
- 长期接触甲基胺 (METH) 是发展高血压的重要危险因素.
- 驱动METH诱导的高血压和相关的血管变化的精确机制尚未完全理解.
研究的目的:
- 为了阐明METH诱导的高血压的潜在机制.
- 研究Sigma1受体 (Sigmar1) 在METH诱导的血管改造和高血压中的作用.
主要方法:
- 建立了一种由METH诱导的高血压的小鼠模型.
- 血管改造,血压 (BP) 和Sigmar1表达在暴露于METH的野生类型 (WT) 和Sigmar1淘汰赛 (KO) 小鼠中进行了评估.
- 在暴露于METH之前,小鼠接受了Sigmar1抗剂 (BD1047) 或激动剂 (PRE-084) 的预治疗.
- 分析了血管光滑肌细胞 (VSMC) 和介质干细胞的分化,原分泌和TGF-β/Smad2/3信号通路.
主要成果:
- 在WT小鼠中,METH暴露导致血压升高,血管重塑与原沉积,以及Sigmar1水平升高.
- 在暴露于METH后,Sigmar1 KO小鼠和接受抗体治疗的小鼠表现出恶化的高血压和血管纤维化.
- 抗激素治疗防止了METH诱导的血压和原蛋白的增加.
- METH诱导VSMC和干细胞分化成肌纤维细胞样细胞,增加原分泌.
- 发现Sigmar1通过抑制METH暴露细胞中的TGF-β/Smad2/3通路来抑制COL1A1表达.
结论:
- 西格玛1在METH诱导的高血压和血管纤维化中发挥着关键作用.
- 西格玛1通过抑制TGF-β/Smad2/3信号通路来缓解METH诱导的血管损伤.
- 向Sigmar1为管理METH诱导的高血压和相关的血管纤维化提供了潜在的治疗策略.
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