Endothelial METRNL determines circulating METRNL level and maintains endothelial function against atherosclerosis

Zheng, Si-Li; Li, Zhiyong; Song, Jie; Wang, Pin; Xu, Jian; Hu, Wenjun; Shi, Yi; Qi, Qi; Miao, Zhu-wei; Guan, Yongjun

doi:10.1016/j.apsb.2022.12.008

Cited by 16 publications

(8 citation statements)

References 52 publications

(127 reference statements)

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“… 14 , 33 , 34 Recent study suggests Metrnl is a therapeutic target against endothelial dysfunction and atherosclerosis. 35 Considering the association of atherosclerosis and blood pressure, 36 the inverse correlation between Metrnl and blood pressure can be well explained. Zhou et al 37 reported that recombinant Metrnl administration or Metrnl-specific overexpression in the kidney relieves renal injuries in diabetic mice.…”

Section: Discussionmentioning

confidence: 99%

Serum Metrnl is Decreased in Metabolic Dysfunction-Associated Fatty Liver Disease: A Case-Control Study

Liu,

Gao,

Tian

et al. 2024

DMSO

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Context Metrnl is a novel adipokine mainly produced by white adipose tissue, which plays important roles in insulin sensitization, and energy homeostasis. However, information about the function of Metrnl in Metabolic dysfunction-associated fatty liver disease (MAFLD) remains unclear. Methods This is a control study, which enrolled 176 adults with MAFLD and 176 normal controls. They were matched in body mass index (BMI), age, and sex. Serum Metrnl was determined by ELISA. Other biochemical data were also collected. Results Compared to the controls, circulating Metrnl was prominently decreased in the MAFLD adults ( P <0.001). Next, binary logistic regression model indicated that sex, waist circumference (WC), triglyceride, γ-gamma glutamyl transferase(γ-GGT), and Metrnl was independently associated with MAFLD. Further, as Metrnl levels elevated across its tertiles, the rate of MAFLD decreased (67.52, 66.95, and 15.38%; P value for trend<0.001). Data from multivariate logistic regression models evidenced that compared with the lowest tertile of Metrnl, the odds ratio of MAFLD was 0.023(95% CI 0.006–0.086, P <0.001) for the highest tertile after adjusting for potential confounders. Besides, area under ROC curve of Metrnl for diagnosis MAFLD was 0.755(95% CI 0.705–0.805). Metrnl was positively correlated with diastolic blood pressure, WC, BMI, systolic blood pressure, γ-GGT, and Creatinine in MAFLD. Finally, we found systolic blood pressure and Creatinine were independently related to serum Metrnl in MAFLD. Conclusion Serum Metrnl is reduced in adult with MAFLD. The results suggest that Metrnl may be a protective factor associated with the pathogenesis of MAFLD.

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Section: Discussionmentioning

confidence: 99%

Serum Metrnl is Decreased in Metabolic Dysfunction-Associated Fatty Liver Disease: A Case-Control Study

Liu,

Gao,

Tian

et al. 2024

DMSO

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“…Inflammation has been demonstrated to impact these connections between endothelial cells, leading to impaired vascular function ( 30 ). Recent experimental evidence highlights that the deficiency of Metrnl results in endothelial cell dysfunction ( 31 ). Moreover, our observations revealed that the overexpression of Metrnl in macrophages plays a protective role in maintaining the integrity of endothelial cell-cell junctions.…”

Section: Discussionmentioning

confidence: 99%

Metrnl inhibits choroidal neovascularization by attenuating the choroidal inflammation via inactivating the UCHL-1/NF-κB signaling pathway

Zhang,

Li,

et al. 2024

Front. Immunol.

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ObjectiveChoroidal neovascularization (CNV) represents the predominant form of advanced wet Age-related Macular Degeneration (wAMD). Macrophages play a pivotal role in the pathological progression of CNV. Meteorin-like (Metrnl), a novel cytokine known for its anti-inflammatory properties in macrophages, is the focus of our investigation into its mechanism of action and its potential to impede CNV progression.MethodsCell viability was evaluated through CCK-8 and EdU assays following Metrnl treatment. Expression levels of inflammatory cytokines and proteins were assessed using quantitative reverse‐transcription polymerase chain reaction(qRT‐PCR), enzyme-linked immunosorbent assay (ELISA), and western blot techniques. Protein-protein interactions were identified through protein mass spectrometry and co-immunoprecipitation (Co‐IP). Additionally, in vivo and in vitro neovascularization models were employed to evaluate angiogenesis.ResultsOur results revealed downregulated Metrnl levels in the choroid-sclera complex of CNV mice, the aqueous humor of wAMD patients, and activated macrophages. Metrnl overexpression demonstrated a reduction in pro-inflammatory cytokine production, influenced endothelial cell function, and suppressed angiogenesis in choroid explants and CNV models. Through protein mass spectrometry and Co‐IP, we confirmed Metrnl binds to UCHL-1 to modulate the NF-κB signaling pathway. This interaction inhibited the transcription and expression of pro-inflammatory cytokines, ultimately suppressing angiogenesis.ConclusionIn summary, our findings indicate that Metrnl down-regulates macrophage pro-inflammatory cytokine secretion via the UCHL-1/NF-κB signaling pathway. This mechanism alleviates the inflammatory microenvironment and effectively inhibits choroidal neovascularization.

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“…The disease process of atherosclerosis is complex and involves several interconnected processes, such as endothelial cell dysfunction, platelet adhesion and activation, and leukocyte function and activation 14 , 44 , 45 , 46 , 47 . Upon biochemical insults to endothelial cells, the expression of inflammatory cytokines is enhanced, which attracts monocytes to congregate at the injury site 48 , 49 , 50 .…”

Section: Emerging Mechanisms Of Action and Cellular Targets For The P...mentioning

confidence: 99%

“…The expression of eNOS can be regulated by different mechanisms, principally through kinase-mediated multisite phosphorylation 76 , 77 . Among various phosphorylation sites, Ser1177 is one of the most studied sites associated with endothelial dysfunction 44 , 78 , 79 , and inhibition of its phosphorylation attenuated the H 2 S-stimulated increase in endothelial NO production 80 . Wang et al.…”

Section: Emerging Mechanisms Of Action and Cellular Targets For The P...mentioning

confidence: 99%

Anti-atherosclerotic effects and molecular targets of ginkgolide B from Ginkgo biloba

Ye,

Wang,

Little

et al. 2024

Acta Pharmaceutica Sinica B

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Endothelial METRNL determines circulating METRNL level and maintains endothelial function against atherosclerosis

Cited by 16 publications

References 52 publications

Serum Metrnl is Decreased in Metabolic Dysfunction-Associated Fatty Liver Disease: A Case-Control Study

Serum Metrnl is Decreased in Metabolic Dysfunction-Associated Fatty Liver Disease: A Case-Control Study

Metrnl inhibits choroidal neovascularization by attenuating the choroidal inflammation via inactivating the UCHL-1/NF-κB signaling pathway

Anti-atherosclerotic effects and molecular targets of ginkgolide B from Ginkgo biloba

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