Metrnl ameliorates myocardial ischemia-reperfusion injury by activating AMPK-mediated M2 macrophage polarization.

IF 6 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Medicine Pub Date : 2025-03-13 DOI:10.1186/s10020-025-01150-4

De-Xin Chen, Yang-Yi Feng, Hai-Yan Wang, Chuang-Hong Lu, De-Zhao Liu, Chen Gong, Yan Xue, Na Na, Feng Huang

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引用次数: 0

Abstract

Background: Meteorin-like hormone (Metrnl) is prominently expressed in activated M2 macrophages and has demonstrated potential therapeutic effects in a range of cardiovascular diseases by modulating inflammatory responses. Nevertheless, its precise role and the underlying mechanisms in myocardial ischemia/reperfusion injury (MI/RI) are not fully understood. This study examined whether Metrnl can mitigate MI/RI through the AMPK-mediated polarization of M2 macrophages.

Methods: In vivo, adeno-associated virus 9 containing the F4/80 promoter (AAV9-F4/80) was utilized to overexpress Metrnl in mouse cardiac macrophages before MI/RI surgery. In vitro, mouse bone marrow-derived macrophages (BMDMs) were treated with recombinant protein Metrnl, and the human cardiomyocyte cell line AC16 was subjected to hypoxia/reoxygenation (H/R) after co-culture with the supernatant of these macrophages. Cardiac function was assessed via echocardiography, H&E staining, and Evans blue-TTC staining. Inflammatory infiltration was evaluated by RT-qPCR and ELISA, apoptosis by Western blotting and TUNEL staining, and macrophage polarization by immunofluorescence staining and flow cytometry.

Results: In vivo, Metrnl overexpression in cardiac macrophages significantly attenuated MI/RI, as evidenced by reduced myocardial infarct size, enhancement of cardiac function, diminished inflammatory cell infiltration, and decreased cardiomyocyte apoptosis. Furthermore, Metrnl overexpression promoted M1 to M2 macrophage polarization. In vitro, BMDMs treated with Metrnl shifted towards M2 polarization, characterized by decreased expression of inflammatory cytokines (IL-1β, MCP-1, TNF-α) and increased expression of the anti-inflammatory cytokine IL-10. Additionally, supernatant from Metrnl-treated macrophages protected AC16 cells from apoptosis under H/R conditions, as evidenced by decreased BAX expression and increased BCL-2 expression. However, these effects of Metrnl were inhibited by the AMPK inhibitor Compound C.

Conclusions: Metrnl alleviates MI/RI by activating AMPK-mediated M2 macrophage polarization to attenuate inflammatory response and cardiomyocyte apoptosis. This study highlights the therapeutic potential of Metrnl in MI/RI, and identifies it as a promising target for the treatment of ischemic heart disease.

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metnl通过激活ampk介导的M2巨噬细胞极化改善心肌缺血再灌注损伤。

背景：流星素样激素（Metrnl）在活化的M2巨噬细胞中显著表达，并通过调节炎症反应在一系列心血管疾病中显示出潜在的治疗作用。然而，其在心肌缺血/再灌注损伤（MI/RI）中的确切作用和潜在机制尚不完全清楚。本研究考察了Metrnl是否可以通过ampk介导的M2巨噬细胞极化来减轻MI/RI。方法：在小鼠心肌/RI手术前，利用含有F4/80启动子的腺相关病毒9 （AAV9-F4/80）在小鼠心脏巨噬细胞中过表达Metrnl。在体外，用重组蛋白Metrnl处理小鼠骨髓源性巨噬细胞（bmmdms），人心肌细胞系AC16与这些巨噬细胞的上清共培养后进行缺氧/再氧化（H/R）。通过超声心动图、H&E染色和Evans blue-TTC染色评估心功能。RT-qPCR和ELISA检测炎症浸润，Western blotting和TUNEL染色检测细胞凋亡，免疫荧光染色和流式细胞术检测巨噬细胞极化。结果：在体内，心肌巨噬细胞中过表达Metrnl可显著降低心肌梗死/RI，表现为心肌梗死面积减小、心功能增强、炎症细胞浸润减少、心肌细胞凋亡减少。此外，Metrnl过表达促进巨噬细胞M1向M2极化。在体外，经Metrnl处理的bmdm向M2极化方向转移，表现为炎症因子（IL-1β、MCP-1、TNF-α）表达降低，抗炎细胞因子IL-10表达升高。此外，经metrnl处理的巨噬细胞上清液在H/R条件下可保护AC16细胞免于凋亡，BAX表达降低，BCL-2表达升高。然而，这些作用被AMPK抑制剂化合物c所抑制。结论：Metrnl通过激活AMPK介导的M2巨噬细胞极化，减轻炎症反应和心肌细胞凋亡，从而减轻MI/RI。本研究强调了Metrnl在MI/RI中的治疗潜力，并将其确定为治疗缺血性心脏病的有希望的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Medicine 医学-生化与分子生物学

CiteScore

8.60

自引率

0.00%

发文量

137

审稿时长

1 months

期刊介绍： Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.