Clemastine fumarate alleviates endoplasmic reticulum stress through the Nur77/GFPT2/CHOP pathway after ischemia/reperfusion in rat hearts

IF 4.7 2区医学 Q2 IMMUNOLOGY International immunopharmacology Pub Date : 2025-03-06 Epub Date: 2025-02-09 DOI:10.1016/j.intimp.2025.114242

Yuling He , Fan Sun , Caixuan Song , Yongxin Liu , Rouguo Wang , Yingmeng Wang , Xiaotong Sun , Zhaodong Juan , Yuansheng Wang

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Abstract

Background and purpose

Clemastine fumarate (CLE) is an H1 receptor (H1R) antagonist that is used clinically to treat various allergic disorders. It blocks histamine release from mast cells and inhibits H1R. Preliminary studies have shown that CLE can reduce myocardial ischemia/reperfusion (I/R) injury. In this study, we confirmed the efficacy of CLE against myocardial I/R injury using in vivo and in vitro examinations.

Experimental approach

To test the efficacy of CLE against myocardial I/R injury, we established a rat model of myocardial hypoxia/reperfusion injury. A series of assessments were conducted to determine cardiac function, measure areas of myocardial infarction, and analyze the histopathological changes. Additionally, we developed a rat model of cardiomyocyte hypoxia/reoxygenation (H/R); in both models, we quantified the expression levels of key markers and cardiac injury-specific proteins to assess the biochemical milieu influenced by CLE treatment.

Key results

Our findings demonstrated that CLE reduced the expression of nerve growth factor-induced gene B (Nur77), glutamine-fructose-6-phosphate transaminase 2 (GFPT2), and C/EBP homologous protein (CHOP) and decreased the area of myocardial infarction and the degree of endoplasmic reticulum stress. CLE pretreatment ameliorated abnormal fibers and myocardial edema and reduced the inflammatory cell infiltration caused by I/R injury. While Nur77 overexpression aggravated cardiac function, these effects were ameliorated by the downregulation of Nur77.

Conclusion and implications

We anticipate that these results validate the hypothesis that CLE mitigates apoptosis and reduces endogenous stress within myocardial cells by modulating Nur77, GFPT2, and CHOP expression. These findings elucidate the therapeutic mechanisms by which CLE alleviates myocardial I/R injury. In addition, they will serve as a new theoretical foundation for developing future treatment strategies and enhancing clinical applications in cardiac care.

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富马酸Clemastine通过Nur77/GFPT2/CHOP通路缓解大鼠心脏缺血/再灌注后内质网应激

背景和目的富马酸塞来马汀（CLE）是一种H1受体（H1R）拮抗剂，临床上用于治疗各种过敏性疾病。它能阻止肥大细胞释放组胺，抑制H1R。初步研究表明CLE可减轻心肌缺血/再灌注（I/R）损伤。在本研究中，我们通过体内和体外实验证实了CLE对心肌I/R损伤的疗效。实验方法：建立大鼠心肌缺氧/再灌注损伤模型，验证CLE对心肌I/R损伤的保护作用。对大鼠进行心功能测定、心肌梗死面积测定、组织病理学变化分析。此外，我们建立了大鼠心肌细胞缺氧/再氧化（H/R）模型；在这两种模型中，我们量化了关键标志物和心脏损伤特异性蛋白的表达水平，以评估CLE治疗对生化环境的影响。本研究结果表明，CLE可降低神经生长因子诱导基因B （Nur77）、谷氨酰胺-果糖-6-磷酸转氨酶2 （GFPT2）和C/EBP同源蛋白（CHOP）的表达，减少心肌梗死面积和内质网应激程度。CLE预处理可改善I/R损伤引起的纤维异常和心肌水肿，减少炎症细胞浸润。虽然Nur77过表达会加重心功能，但下调Nur77可改善这些影响。结论和意义我们预期这些结果验证了CLE通过调节Nur77、GFPT2和CHOP表达来减轻心肌细胞凋亡和内源性应激的假设。这些发现阐明了CLE减轻心肌I/R损伤的治疗机制。此外，它们将为制定未来的治疗策略和加强心脏护理的临床应用提供新的理论基础。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.