Department of Anesthesiology, Hunan Provincial People's Hospital (The first-affiliated hospital of Hunan normal university), China.
J Toxicol Sci. 2023;48(6):345-354. doi: 10.2131/jts.48.345.
Liver ischemia reperfusion (IR) injury induces hepatic stellate cell (HSC) activation and liver fibrosis. Propofol (PRO) possesses a positive protective effect on liver ischemia reperfusion injury. We aimed to investigate PRO function and mechanism in IR-induced liver fibrosis. A mice model of liver IR was established. Hematoxylin-eosin (HE) staining was utilized to evaluate liver tissue's pathological changes. Masson staining was applied to evaluate liver fibrosis. The expression level of α-SMA was measured by immunohistochemical (IHC). The expressions of lncRNA HOXA11-AS (HOXA11-AS), PTBP1, HDAC4, α-SMA, COL1A1 and Fibronectin were tested by qRT-PCR or Western blot. The commercial kits detected alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations in serum. Enzyme-linked immunosorbent assay (ELISA) measured TNF-α and IL-6 levels. The binding relationship between HOXA11-AS, PTBP1 and HDAC4 was verified by RNA immunoprecipitation (RIP). Our results showed that PRO alleviated liver fibrosis and the inflammation in IR-induced mice. PRO decreased the expression levels of HOXA11-AS, PTBP1 and HDAC4. Furthermore, HOXA11-AS overexpression abolished the protective effect of PRO against liver fibrosis in mice with IR-disposed. HOXA11-AS interacted with PTBP1 to regulate HDAC4 level and prevented its degradation in JS-1 cells. HDAC4 silencing eliminated the regulatory of HOXA11-AS overexpression on fibrosis and inflammation in IR-induced mice PRO inhibited HOXA11-AS expression to regulate HDAC4, thereby influencing liver fibrosis and inflammation induced by IR. It suggesting that PRO plays a protective role in liver fibrosis induced by ischemia-reperfusion in mice by regulating HOXA11-AS/PTBP1/HDAC4 axis.
肝缺血再灌注 (IR) 损伤诱导肝星状细胞 (HSC) 活化和肝纤维化。异丙酚 (PRO) 对肝缺血再灌注损伤具有积极的保护作用。我们旨在研究 PRO 在 IR 诱导的肝纤维化中的作用和机制。建立了小鼠肝 IR 模型。使用苏木精-伊红 (HE) 染色评估肝组织的病理变化。通过 Masson 染色评估肝纤维化。免疫组织化学 (IHC) 测定α-SMA 的表达水平。通过 qRT-PCR 或 Western blot 检测 lncRNA HOXA11-AS (HOXA11-AS)、PTBP1、HDAC4、α-SMA、COL1A1 和纤维连接蛋白的表达。商业试剂盒检测血清中丙氨酸氨基转移酶 (ALT) 和天冬氨酸氨基转移酶 (AST) 浓度。酶联免疫吸附试验 (ELISA) 测量 TNF-α 和 IL-6 水平。通过 RNA 免疫沉淀 (RIP) 验证 HOXA11-AS、PTBP1 和 HDAC4 之间的结合关系。我们的结果表明，PRO 减轻了 IR 诱导的小鼠肝纤维化和炎症。PRO 降低了 HOXA11-AS、PTBP1 和 HDAC4 的表达水平。此外，HOXA11-AS 过表达消除了 PRO 对 IR 处理小鼠肝纤维化的保护作用。HOXA11-AS 与 PTBP1 相互作用调节 HDAC4 水平并防止其在 JS-1 细胞中降解。HDAC4 沉默消除了 HOXA11-AS 过表达对 IR 诱导的小鼠纤维化和炎症的调节作用。PRO 通过调节 HOXA11-AS/PTBP1/HDAC4 轴抑制 HOXA11-AS 表达来调节 HDAC4，从而影响 IR 诱导的肝纤维化和炎症。这表明 PRO 通过调节 HOXA11-AS/PTBP1/HDAC4 轴在小鼠缺血再灌注引起的肝纤维化中发挥保护作用。
