Liu Xueru, Shui Guojing, Wang Yan, Chen Tangting, Zhang Peng, Liu Li, Li Chunhong, Li Tao, Wang Xiaobin
Department of Anesthesiology, Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.
Key Laboratory of Medical Electrophysiology of the Ministry of Education, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.
Int J Mol Med. 2025 Apr;55(4). doi: 10.3892/ijmm.2025.5498. Epub 2025 Jan 31.
Remimazolam (Rema) is a novel anesthetic that is widely used in anesthesia and sedation in critically ill patients. Notably, Rema exerts effects in patients through activation of the γ‑aminobutyric acid (GABA) receptor. GABA may alleviate myocardial ischemia/reperfusion (I/R) injury; however, the impact of Rema and underlying molecular mechanism in myocardial I/R injury remain to be fully understood. Therefore, the present study aimed to investigate the effects of Rema on cardiac I/R injury and to determine the underlying mechanisms. An acute myocardial I/R model was established by ligating the left anterior descending artery in adult male C57BL/6 mice (8‑10 weeks). Cultured Raw264.7 cells treated with lipopolysaccharide (LPS) were also used to investigate the effect of Rema on macrophages. The results of the present study revealed that Rema improved I/R‑induced cardiac dysfunction by increasing the ejection fraction value and reducing the myocardial infarction area. In addition, Rema also alleviated I/R‑induced cardiac inflammatory cell infiltration based on H&E and immunofluorescence staining. Transmission electron microscopy and ROS measurements showed that Rema improved I/R‑induced mitochondrial structural disruption and oxidative stress in cardiomyocytes. Transcriptomics analysis and reverse transcription‑quantitative PCR revealed that Rema alleviated I/R‑induced release of inflammatory factors and cytokines by inhibiting the expression of IL‑1β, IL‑6, C‑C chemokine receptor 2 and C‑X‑C motif chemokine ligand 5. Rema also inhibited I/R‑induced CD68+ cell proliferation, IL‑1β release, and NOD‑like receptor thermal protein domain associated protein 3 (NLRP3) and IL‑1β expression. The results of assays revealed that Rema inhibited LPS‑induced increases in IL‑1β, IL‑6 and TNF‑α expression and release in cultured RAW264.7 macrophages. In conclusion, the present study revealed that Rema may alleviate I/R‑induced cardiac dysfunction and myocardial injury by inhibiting oxidative stress and inflammatory responses via the NLRP3/IL‑1β pathway.
瑞马唑仑（Rema）是一种新型麻醉剂，广泛应用于危重症患者的麻醉和镇静。值得注意的是，Rema通过激活γ-氨基丁酸（GABA）受体对患者产生作用。GABA可能减轻心肌缺血/再灌注（I/R）损伤；然而，Rema对心肌I/R损伤的影响及其潜在分子机制仍有待充分了解。因此，本研究旨在探讨Rema对心脏I/R损伤的影响并确定其潜在机制。通过结扎成年雄性C57BL/6小鼠（8-10周）的左前降支动脉建立急性心肌I/R模型。用脂多糖（LPS）处理的培养Raw264.7细胞也用于研究Rema对巨噬细胞的作用。本研究结果显示，Rema通过增加射血分数值和减少心肌梗死面积改善I/R诱导的心脏功能障碍。此外，基于苏木精-伊红（H&E）和免疫荧光染色，Rema还减轻了I/R诱导的心脏炎性细胞浸润。透射电子显微镜和活性氧（ROS）测量表明，Rema改善了I/R诱导的心肌细胞线粒体结构破坏和氧化应激。转录组学分析和逆转录定量聚合酶链反应显示，Rema通过抑制白细胞介素-1β（IL-1β）、白细胞介素-6、C-C趋化因子受体2和C-X-C基序趋化因子配体5的表达减轻I/R诱导的炎性因子和细胞因子释放。Rema还抑制I/R诱导的CD68+细胞增殖、IL-1β释放以及NOD样受体热蛋白结构域相关蛋白3（NLRP3）和IL-1β表达。实验结果显示，Rema抑制LPS诱导的培养RAW264.7巨噬细胞中IL-1β、IL-6和肿瘤坏死因子-α（TNF-α）表达及释放增加。总之，本研究表明，Rema可能通过NLRP3/IL-1β途径抑制氧化应激和炎症反应，从而减轻I/R诱导的心脏功能障碍和心肌损伤。
