Genetic and epigenetic regulation of cortactin (CTTN) by inflammatory factors and mechanical stress in human lung endothelial cells.

IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Bioscience Reports Pub Date : 2024-09-25 DOI:10.1042/BSR20231934
Xiaoguang Sun, Belinda Sun, Saad Sammani, Steven M Dudek, Patrick Belvitch, Sara M Camp, Donna Zhang, Christian Bime, Joe G N Garcia
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Abstract

Rationale: Cortactin, an actin-binding cytoskeletal protein, plays a crucial role in maintaining endothelial cell (EC) barrier integrity and regulating vascular permeability. The gene encoding cortactin, CTTN, is implicated in various lung inflammatory disorders. Despite this, the transcriptional regulation of CTTN by inflammatory stimuli and promoter SNPs remains unexplored.

Methods: We transfected human lung ECs with a full-length CTTN promoters linked to a luciferase reporter to measure promoter activity. SNP-containing CTTN promoter was created via site-directed mutagenesis. Transfected ECs were exposed to LPS (PAMP), TNF-α (cytokine), cyclic stretch (CS), FG-4592 (HIF-inducer), NRF2 (anti-oxidant modulator), FTY-(S)-phosphate (endothelial barrier enhancer), and 5'-Aza (demethylation inducer). Immunohistochemistry was used to assess cortactin expression in mouse lungs exposed to LPS.

Results: LPS, TNF-α, and 18%CS significantly increased CTTN promoter activities in a time-dependent manner (P<0.05). The variant rs34612166 (-212T/C) markedly enhanced LPS- and 18%CS- induced CTTN promoter activities (P<0.05). FG-4592 significantly boosted CTTN promoter activities (P<0.01), which were partially inhibited by HIF1α (KC7F2) and HIF2α (PT2385) inhibitors (P<0.05). NRF2 activator Bixin increased CTTN promoter activities, whereas NRF2 inhibitor Brusatol reduced them (P<0.05). 5'-Aza increased CTTN promoter activities by 2.9-fold (P<0.05). NF-κB response element mutations significantly reduced CTTN promoter activities response to LPS and TNFα. FTY-(S)-phosphate significantly increased CTTN promoter activities in 24 h. In vivo, cortactin levels were significantly elevated in inflammatory mouse lungs exposed to LPS for 18 h.

Conclusion: CTTN transcriptional is significantly influenced by inflammatory factors and promoter variants. Cortactin, essential in mitigating inflammatory edema, presents a promising therapeutic target to alleviate severe inflammatory disorders.

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人肺内皮细胞中炎症因子和机械应力对 Cortactin (CTTN) 的遗传和表观遗传调控
理由Cortactin是一种肌动蛋白结合细胞骨架蛋白,在维持内皮细胞(EC)屏障完整性和调节血管通透性方面起着至关重要的作用。编码 Cortactin 的基因 CTTN 与多种肺部炎症疾病有关。尽管如此,CTTN 受炎症刺激和启动子 SNPs 的转录调控仍未得到研究:我们用连接荧光素酶报告基因的全长 CTTN 启动子转染人肺 EC,以测量启动子活性。含 SNP 的 CTTN 启动子是通过定点突变产生的。转染的心肌暴露于 LPS(PAMP)、TNF-α(细胞因子)、环状拉伸(CS)、FG-4592(HIF 诱导剂)、NRF2(抗氧化调节剂)、FTY-(S)-磷酸(内皮屏障增强剂)和 5'-Aza(去甲基化诱导剂)。免疫组化技术用于评估暴露于 LPS 的小鼠肺部的 cortactin 表达:结果:LPS、TNF-α和18%CS以时间依赖性方式显著增加了CTTN启动子的活性(p结论:CTTN转录受LPS、TNF-α和18%CS的显著影响:CTTN转录受炎症因子和启动子变体的影响很大。Cortactin对减轻炎症性水肿至关重要,是缓解严重炎症性疾病的一个很有前景的治疗靶点。
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来源期刊
Bioscience Reports
Bioscience Reports 生物-细胞生物学
CiteScore
8.50
自引率
0.00%
发文量
380
审稿时长
6-12 weeks
期刊介绍: Bioscience Reports provides a home for sound scientific research in all areas of cell biology and molecular life sciences. Since 2012, Bioscience Reports has been fully Open Access and publishes all papers under the liberal CC BY licence, giving the life science community quality research to share and discuss.Content before 2012 is subscription-only, and is accessible via archive purchase. Articles are assessed on soundness, providing a home for valid findings and data. We welcome papers that span disciplines (e.g. chemistry, medicine), including papers describing: -new methodologies -tools and reagents to probe biological questions -mechanistic details -disease mechanisms -metabolic processes and their regulation -structure and function -bioenergetics
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