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Chronic vascular pathogenesis results in the reduced serum Metrnl levels in ischemic stroke patients

Acta Pharmacologica Sinica volume 45, pages 914–925 (2024)Cite this article

Abstract

Metrnl is a secreted protein involved in neurite outgrowth, insulin sensitivity, immunoinflammatory responses, blood lipids and endothelial protection. In this study, we investigated the role of Metrnl in ischemic stroke. Fifty-eight ischemic stroke patients (28 inpatient patients within 2 weeks of onset and 30 emergency patients within 24 h of onset) and 20 healthy controls were enrolled. Serum Metrnl was measured by enzyme-linked immunosorbent assay. We showed that serum Metrnl levels were significantly reduced in both inpatient and emergency patient groups compared with the controls. Different pathological causes for ischemic stroke such as large artery atherosclerosis and small artery occlusion exhibited similar reduced serum Metrnl levels. Transient ischemic attack caused by large artery atherosclerosis without brain infarction also had lower serum Metrnl levels. Metrnl was correlated with some metabolic, inflammatory and clotting parameters. Reduced serum Metrnl was associated with the severity of intracranial arterial stenosis and the presence of ischemic stroke. In order to elucidate the mechanisms underlying the reduced serum Metrnl levels, we established animal models of ischemic stroke in normal mice, atherosclerotic apolipoprotein E-knockout mice and Metrnl-knockout mice by middle cerebral artery occlusion (MCAO) using intraluminal filament or electrocoagulation. We demonstrated that serum Metrnl levels were significantly lower in atherosclerosis mice than normal mice, whereas acute ischemic stroke injury in normal mice and atherosclerosis mice did not alter serum Metrnl levels. Metrnl knockout did not affect acute ischemic stroke injury and death. We conclude that reduced serum Metrnl levels are attributed to the chronic vascular pathogenesis before the onset of ischemic stroke. Metrnl is a potential target for prevention of ischemic stroke.

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Fig. 1: Serum Metrnl concentrations in all human participants.
Fig. 2: Representative imaging data of different pathological causes in ischemic stroke.
Fig. 3: Association of serum Metrnl levels with the severity of intracranial arterial stenosis and the presence of ischemic stroke.
Fig. 4: Serum Metrnl concentrations in C57BL/6 and Apo E knockout (ApoE−/−) mice with Sham or middle cerebral artery occlusion (MCAO) operation.
Fig. 5: Effect of Metrnl on acute ischemic stroke injury.

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Acknowledgements

The authors thank all participating colleagues, nurses, imaging and laboratory technicians and are grateful to all subjects for their participation in the study. This work was supported by the National Natural Science Foundation of China Major Project (82030110, 82330117 and 81730098 to CYM).

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Author notes

  1. These authors contributed equally: Zhu-wei Miao, Nuo Wang, Wen-jun Hu, Si-li Zheng.

Authors and Affiliations

  1. Department of Pharmacology, Second Military Medical University/Naval Medical University, Shanghai, 200433, China

    Zhu-wei Miao, Wen-jun Hu, Si-li Zheng, Dong-sheng Wang, Fu-qiang Chang, Zhi Wang, Jia-sheng Tian & Chao-yu Miao

  2. Department of Neuroloy and Neurovascular Center, The First Affiliated Hospital (Changhai Hospital), Second Military Medical University/Naval Medical University, Shanghai, 200433, China

    Nuo Wang & Tao Wu

  3. Department of Pharmacy, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China

    Xiao-hui Dong

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Contributions

All authors contribute to this paper. Study concept and design: CYM and TW. Clinical data and statistical analysis: ZWM, NW, WJH, FQC, TW, and CYM. Animal data and statistical analysis: ZWM, WJH, SLZ, DSW, ZW, JST, XHD, and CYM. Drafting of the manuscript: ZWM, NW, WJH, and SLZ. Revision of the manuscript: CYM and TW.

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Correspondence to Tao Wu or Chao-yu Miao.

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Miao, Zw., Wang, N., Hu, Wj. et al. Chronic vascular pathogenesis results in the reduced serum Metrnl levels in ischemic stroke patients. Acta Pharmacol Sin 45, 914–925 (2024). https://doi.org/10.1038/s41401-023-01204-5

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