Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, PR China.
Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, PR China.
Int Immunopharmacol. 2024 May 30;133:112073. doi: 10.1016/j.intimp.2024.112073. Epub 2024 Apr 17.
Myocarditis is an important clinical issue which lacks specific treatment by now. Ivermectin (IVM) is an inhibitor of importin α/β-mediated nuclear translocation. This study aimed to explore the therapeutic effects of IVM on acute myocarditis.
Mouse models of coxsackie B3 virus (CVB3) infection-induced myocarditis and experimental autoimmune myocarditis (EAM) were established to evaluate the effects of IVM. Cardiac functions were evaluated by echocardiography and Millar catheter. Cardiac inflammatory infiltration was assessed by histological staining. Cytometric bead array and quantitative real-time PCR were used to detect the levels of pro-inflammatory cytokines. The macrophages and their M1/M2 polarization were analyzed via flow cytometry. Protein expression and binding were detected by co-immunoprecipitation, Western blotting and histological staining. The underlying mechanism was verified in vitro using CVB3-infected RAW264.7 macrophages. Cyclic polypeptide (cTN50) was synthesized to selectively inhibit the nuclear translocation of NF-κB/p65, and CVB3-infected RAW264.7 cells were treated with cTN50.
Increased expression of importin β was observed in both models. IVM treatment improved cardiac functions and reduced the cardiac inflammation associated with CVB3-myocarditis and EAM. Furthermore, the pro-inflammatory cytokine (IL-1β/IL-6/TNF-α) levels were downregulated via the inhibition of the nuclear translocation of NF-κB/p65 in macrophages. IVM and cTN50 treatment also inhibited the nuclear translocation of NF-κB/p65 and downregulated the expression of pro-inflammatory cytokines in RAW264.7 macrophages.
Ivermectin inhibits the nuclear translocation of NF-κB/p65 and the expression of major pro-inflammatory cytokines in myocarditis. The therapeutic effects of IVM on viral and non-viral myocarditis models suggest its potential application in the treatment of acute myocarditis.
心肌炎是目前缺乏特定治疗方法的重要临床问题。伊维菌素（IVM）是一种抑制核输入载体蛋白（importin α/β）介导的核转运的抑制剂。本研究旨在探讨 IVM 对急性心肌炎的治疗作用。
建立柯萨奇 B3 病毒（CVB3）感染诱导的心肌炎和实验性自身免疫性心肌炎（EAM）小鼠模型，评估 IVM 的作用。通过超声心动图和 Millar 导管评估心功能。通过组织学染色评估心肌炎症浸润。采用细胞因子检测试剂盒和实时定量 PCR 检测促炎细胞因子水平。通过流式细胞术分析巨噬细胞及其 M1/M2 极化。通过共免疫沉淀、Western blot 和组织学染色检测蛋白表达和结合。在体外使用 CVB3 感染的 RAW264.7 巨噬细胞验证潜在机制。合成环肽（cTN50）以选择性抑制 NF-κB/p65 的核转运，并将 cTN50 用于 CVB3 感染的 RAW264.7 细胞。
在两种模型中均观察到 importin β 的表达增加。IVM 治疗改善了心脏功能，减轻了与 CVB3 心肌炎和 EAM 相关的心脏炎症。此外，通过抑制巨噬细胞中 NF-κB/p65 的核转运，下调了促炎细胞因子（IL-1β/IL-6/TNF-α）水平。IVM 和 cTN50 治疗还抑制了 NF-κB/p65 的核转运，并下调了 RAW264.7 巨噬细胞中促炎细胞因子的表达。
伊维菌素抑制 NF-κB/p65 的核转运和心肌炎中主要促炎细胞因子的表达。IVM 对病毒性和非病毒性心肌炎模型的治疗作用表明其在治疗急性心肌炎方面具有潜在应用。
