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由于R213G多态的SOD3表达的重新分配会影响肺间歇性巨细胞的重编程,以应对缺氧

Caitlin V Lewis^1,2, Anastacia M Garcia³, Samuel D Burciaga^1,2

¹Cardiovascular Pulmonary Research Laboratories, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States.

Physiological genomics

|September 23, 2024

概括

超氧化物脱酶3 (SOD3) 中的R213G单核酸多态 (SNP) 在缺氧期间不会增加肺巨细胞,但会改变它们的代谢和炎症反应,恶化肺高血压 (PH). 这种SOD3变体损害了巨细胞对低氧压力的代谢适应,阻碍了炎症的解决.

科学领域:

肺高血压的发病因子肺高血压的发病因子
巨细胞生物学和新陈代谢
细胞外矩阵重塑细胞外矩阵重塑

背景情况:

细胞外超氧化物失突酶 (SOD3) 水平在肺高血压 (PH) 中降低.
SOD3 R213G单核酸多态 (SNP) 将SOD3从细胞外基质 (ECM) 迁移到细胞外液体中,增加心血管疾病风险并恶化缺氧PH.
间歇性巨细胞 (IMs) 在PH发育中起着至关重要的作用.

研究的目的:

为了调查R213G SOD3 SNP是否影响间歇性巨细胞 (IM) 积累,以应对低氧.
确定R213G SOD3 SNP在低氧条件下如何影响IM重编程.
阐明R213G SNP对长期缺氧期间巨细胞代谢和炎症反应的影响.

主要方法:

使用R213G突变和野生型 (WT) 鼠标暴露于低性缺氧.
采用流细胞计量来量化IM群体在不同的时间点 (4和14天).
进行RNA测序和Agilent海马对隔离的IM进行测定,以分析基因表达和代谢功能 (糖解).

主要成果:

在R213G和WT小鼠中,缺氧暂时增加了IMs;R213G SNP没有加剧IM积累.
RNA测序显示,来自R213G小鼠的低氧暴露的IMs表现出与ECM相关和促炎途径的激活.
与WT IMs相比,R213G IMs显示出淡的抗炎反应,缺乏代谢重塑,特别是受损的葡萄糖分解上调.

结论:

R213G SOD3 SNP通过改变巨细胞的表型而不是增加它们的数量来加剧慢性缺氧PH.
R213G巨细胞表现出对低氧的代谢适应受损,导致持续的炎症信号传递和炎症分辨率降低.
这些发现强调了巨细胞在PH中的代谢重编程的关键作用,并表明了与氧化还原调节和ECM通路相关的潜在治疗点.

关键词:

缺氧缺氧是指缺氧的情况.免疫代谢的免疫代谢.巨细胞的重编程肺高血压是一种肺高血压.氧化还原信号传递.

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