Department of Hepatobiliary and Pancreatic Surgery, Union Shenzhen Hospital, Huazhong University of Science and Technology, 518056 Shenzhen, Guangdong, China.
Discov Med. 2024 Aug;36(187):1721-1731. doi: 10.24976/Discov.Med.202436187.158.
Hyperlipidemia is one of the main causes of aggravated hepatic ischemia-reperfusion injury (IRI). Simvastatin (SIM), a lipid-lowering drug, has been shown to effectively alleviate IRI caused by hyperlipidemia. However, the regulatory mechanism by which SIM alleviates hyperlipidemia-induced hepatic IRI is still not clear. This study aims to explore the potential mechanisms of SIM in inhibiting hyperlipidemia-induced hepatic IRI, providing new therapeutic strategies for the alleviation of hepatic IRI.
An animal model of hyperlipidemia was induced by feeding mice a high-fat diet for 8 weeks. Subsequently, a hepatic IRI animal model of hyperlipidemia was established by occluding the hepatic artery and portal vein for one hour, followed by reperfusion for 6 or 12 h. Enzyme linked immunosorbent assay, Western blotting, hematoxylin-eosin (H&E) staining, immunohistochemistry, immunofluorescence, and Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling assay, were used to evaluate liver injury, neutrophil extracellular traps (NETs) formation, and related molecular mechanisms.
Hepatic IRI was accelerated by hyperlipidemia, which enhanced the expression of oxidized low-density lipoprotein (oxLDL) and Macrophage-1antigen (Mac-1), leading to the promotion of NETs formation and apoptosis of liver cells. The administration of simvastatin reduced the levels of oxLDL and Mac-1, decreased the formation of NETs, and alleviated hepatic IRI induced by hyperlipidemia.
Simvastatin reduced hyperlipidemia-induced hepatic IRI by inhibiting the formation of NETs through the regulation of the oxLDL/Mac-1 pathway.
高血脂是加重肝缺血再灌注损伤（IRI）的主要原因之一。降脂药辛伐他汀（SIM）已被证明能有效缓解高血脂引起的 IRI。然而，SIM 缓解高血脂诱导的肝 IRI 的调节机制尚不清楚。本研究旨在探讨 SIM 抑制高血脂诱导的肝 IRI 的潜在机制，为减轻肝 IRI 提供新的治疗策略。
用高脂饮食喂养小鼠 8 周诱导动物高血脂模型。然后，通过阻断肝动脉和门静脉 1 小时，再灌注 6 或 12 小时建立高血脂诱导的肝 IRI 动物模型。酶联免疫吸附试验、Western blot、苏木精-伊红（H&E）染色、免疫组织化学、免疫荧光和末端脱氧核苷酸转移酶介导的缺口末端标记法，用于评估肝损伤、中性粒细胞胞外陷阱（NETs）形成和相关分子机制。
高血脂加速了肝 IRI，增强了氧化低密度脂蛋白（oxLDL）和巨噬细胞-1 抗原（Mac-1）的表达，促进了 NETs 的形成和肝细胞凋亡。辛伐他汀的给药降低了 oxLDL 和 Mac-1 的水平，减少了 NETs 的形成，并缓解了高血脂引起的肝 IRI。
辛伐他汀通过调节 oxLDL/Mac-1 通路抑制 NETs 的形成，减轻高血脂诱导的肝 IRI。
