Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Digestive Organ Transplantation & Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
Henan Key Laboratory of Digestive Organ Transplantation & Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
Biochim Biophys Acta Mol Basis Dis. 2024 Dec;1870(8):167490. doi: 10.1016/j.bbadis.2024.167490. Epub 2024 Sep 4.
Vascular endothelial inflammation is crucial in hepatic ischemia-reperfusion injury (IRI). Our previous research has shown that connective tissue growth factor (CTGF), secreted by endothelial cells, protects against acute liver injury, but its upstream mechanism is unclear. We aimed to clarify the protective role of CTGF in endothelial cell inflammation during IRI and reveal the regulation between endoplasmic reticulum stress-induced activating transcription factor 6 (ATF6) and CTGF. Hypoxia/reoxygenation in endothelial cells, hepatic IRI in mice and clinical specimens were used to examine the relationships between CTGF and inflammatory factors and determine how ATF6 regulates CTGF and reduces damage. We found that activating ATF6 promoted CTGF expression and reduced liver damage in hepatic IRI. In vitro, activated ATF6 upregulated CTGF and downregulated inflammation, while ATF6 inhibition had the opposite effect. Dual-luciferase assays and chromatin immunoprecipitation confirmed that activated ATF6 binds to the CTGF promoter, enhancing its expression. Activated ATF6 increases CTGF and reduces extracellular regulated protein kinase 1/2 (ERK1/2) phosphorylation, decreasing inflammatory factors. Conversely, inhibiting ATF6 decreases CTGF and increases the phosphorylation of ERK1/2, increasing inflammatory factor levels. ERK1/2 inhibition reverses this effect. Clinical samples have shown that CTGF increases after IRI, inversely correlating with inflammatory cytokines. Therefore, ATF6 activation during liver IRI enhances CTGF expression and reduces endothelial inflammation via ERK1/2 inhibition, providing a novel target for diagnosing and treating liver IRI.
血管内皮炎症在肝缺血再灌注损伤（IRI）中至关重要。我们之前的研究表明，内皮细胞分泌的结缔组织生长因子（CTGF）可防止急性肝损伤，但上游机制尚不清楚。我们旨在阐明 CTGF 在IRI 期间内皮细胞炎症中的保护作用，并揭示内质网应激诱导的激活转录因子 6（ATF6）与 CTGF 之间的调节关系。内皮细胞缺氧/复氧、小鼠肝 IRI 和临床标本用于研究 CTGF 与炎症因子之间的关系，并确定 ATF6 如何调节 CTGF 并减轻损伤。我们发现激活 ATF6 可促进 CTGF 表达并减轻肝 IRI 中的肝损伤。在体外，激活的 ATF6 上调 CTGF 并下调炎症，而 ATF6 抑制则产生相反的效果。双荧光素酶报告基因和染色质免疫沉淀实验证实激活的 ATF6 结合 CTGF 启动子，增强其表达。激活的 ATF6 增加 CTGF 并减少细胞外调节蛋白激酶 1/2（ERK1/2）磷酸化，减少炎症因子。相反，抑制 ATF6 会降低 CTGF 并增加 ERK1/2 的磷酸化，从而增加炎症因子水平。ERK1/2 抑制可逆转此作用。临床样本表明，IRI 后 CTGF 增加，与炎症细胞因子呈负相关。因此，肝 IRI 期间 ATF6 的激活通过 ERK1/2 抑制增强 CTGF 表达并减轻内皮炎症，为诊断和治疗肝 IRI 提供了新的靶点。
