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首页> 外文期刊>Biochimica et biophysica acta. Molecular basis of disease: BBA >Lipopolysaccharide and interferon-gamma team up to activate HIF-1 alpha via STAT1 in normoxia and exhibit sex differences in human aortic valve interstitial cells
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Lipopolysaccharide and interferon-gamma team up to activate HIF-1 alpha via STAT1 in normoxia and exhibit sex differences in human aortic valve interstitial cells

机译：脂多糖和干扰素 - γ团队在常氧中通过Stat1激活HIF-1α，表现出人主动脉瓣间质细胞的性别差异

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In early stages of calcific aortic valve disease (CAVD), immune cells infiltrate into the valve leaflets and release cytokines such as interferon (IFN)-gamma. IFN-gamma has context-dependent direct effects, and also regulates other immune pathways. The purpose of this study was addressing the effects of IFN-gamma on human aortic valve interstitial cells (AVICs), focusing on the pathogenic processes underlying CAVD. Strikingly, under normoxic conditions, IFN-gamma induced hypoxia inducible factor (HIF)-1 alpha expression, an effect strongly potentiated by the Toll-like receptor (TLR)-4 ligand lipopolysaccharide (LPS). Immunodetection studies confirmed the nuclear translocation of HIFI a. Gene silencing showed that HIF-1 alpha expression is dependent on signal transducer and activator of transcription (STAT)-1 expression. Consistent with HIF-1 alpha induction, the secretion of the endothelial growth factor was detected by ELISA, and downregulation of the antiangiogenic factor chondromodulin-1 gene was observed by qPCR. Results also disclosed IFN-gamma as a proinflammatory cytokine that cooperates with LPS to induce the expression of adhesion molecules, prostaglandin E-2 and interleukins. Moreover, IFN-gamma induced an osteogenic phenotype and promoted in vitro calcification that were markedly potentiated by LPS. Pharmacological experiments disclosed the involvement of Janus Kinases (JAK)/STATs as well as ERK/HIF-1 alpha routes on the induction of calcification. Notably, IFN-gamma receptor I expression, as well as ERK/HIF-1 alpha activation, and the subsequent responses were more robust in male AVICs. This is the first report uncovering an immune and non-hypoxic activation of HIF-1 alpha via STAT1 in AVIC. The aforementioned results and the sex-differential responses may be potentially relevant to better understand CAVD pathogenesis.
机译：在钙化主动脉瓣病（CAVD）的早期阶段，免疫细胞浸润到瓣膜小叶中并释放细胞因子，例如干扰素（IFN）-Gamma。 IFN-Gamma具有上下文依赖性直接效果，还调节其他免疫途径。本研究的目的是解决IFN-GAMMA对人主动脉瓣间质细胞（AVICS）的影响，重点是CAVD下面的致病过程。令人惊讶的是，在常氧的条件下，IFN-Gamma诱导的缺氧诱导因子（HIF）-1α表达，通过Toll样受体（TLR）-4配体脂多糖（LPS）强烈增强的效果。免疫检测研究证实了HIFI A的核迁移。基因沉默表明HIF-1α表达取决于信号传感器和转录激活剂（统计）-1表达。与HIF-1α感应一致，ELISA检测内皮生长因子的分泌，并通过QPCR观察到抗血管生成因子软骨调节蛋白-1基因的下调。结果还公开了IFN-GAMMA作为促炎细胞因子，其与LPS配合，诱导粘附分子，前列腺素E-2和白细胞介素的表达。此外，IFN-GAMMA诱导骨质发生表型并促进了LPS明显增强的体外钙化。药理学实验公开了Janus激酶（Jak）/统计阶段以及ERK / HIF-1α途径对钙化诱导的影响。值得注意的是，IFN-Gamma受体I表达，以及ERK / HIF-1α激活，随后的响应在雄性航空中更加稳健。这是通过AVIC中通过Stat1揭示HIF-1α的免疫和非缺氧活化的第一个报告。上述结果和性别差异反应可能与更好地理解CAVD发病机制可能相关。

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