Meteorin-Like (METRNL) Attenuates Myocardial Ischemia/Reperfusion Injury-Induced Cardiomyocytes Apoptosis by Alleviating Endoplasmic Reticulum Stress Via Activation of AMPK-PAK2 Signaling in H9C2 Cells

Overview

Journal Med Sci Monit

Specialties General Medicine
Pathology

Date 2020 Jun 29

PMID 32594095

Citations 17

Authors

Ling Xu

Yinlian Cai

Yaoguo Wang

Chaoxiang Xu

Affiliations

Soon will be listed here.

Abstract

BACKGROUND Myocardial ischemia mediates the progression of multiple cardiovascular diseases and leads to serious damage to the morphology, function, and metabolism of cardiomyocytes. The serum level of the hormone Meteorin-like (METRNL) was lower in patients with coronary artery disease and was negatively correlated with inflammatory cytokines. The aim of the present study was to determine the relationship between METRNL and myocardial ischemia/reperfusion (MI/R) injury, and investigate the molecular mechanisms implicated the pathogenesis of myocardial ischemia. MATERIAL AND METHODS In the present study, H9C2 cells underwent oxygen-glucose deprivation and reperfusion (OGD/R) treatment to establish a MI/R cell model. Quantitative real-time polymerase chain reaction was performed to analyze the expression of target gene. Western blot was used to evaluate the protein expression. Cell Counting Kit-8 assay was employed to detect the cell viability. Enzyme-linked immunosorbent assay was carried out to determine the levels of inflammatory cytokines. Finally, flow cytometry and TUNEL staining were used to detect the apoptotic levels of cardiomyocytes. RESULTS The results showed that the expression of METRNL was downregulated in H9C2 cells during OGD/R. Interestingly, METRNL overexpression inhibited the inflammation, apoptosis and endoplasmic reticulum stress in H9C2 cells during OGD/R, which were totally reversed by PAK2 silencing. In addition, METRNL overexpression induced activation of AMPK-PAK2 signaling cascade. CONCLUSIONS METRNL attenuates MI/R injury-induced cardiomyocytes apoptosis by alleviating endoplasmic reticulum stress via activation of AMPK-PAK2 signaling in H9C2 cells. Our findings support that METRNL might be a promising target for treatment of myocardial ischemia in the future.

Citing Articles

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

Chen D, Feng Y, Wang H, Lu C, Liu D, Gong C Mol Med. 2025; 31(1):98.

PMID: 40082768 PMC: 11907862. DOI: 10.1186/s10020-025-01150-4.

Metrnl and Cardiomyopathies: From Molecular Mechanisms to Therapeutic Insights.

Xu M, Liu X, Lu L, Li Z J Cell Mol Med. 2025; 29(2):e70371.

PMID: 39853716 PMC: 11756984. DOI: 10.1111/jcmm.70371.

Adipokines and their potential impacts on susceptibility to myocardial ischemia/reperfusion injury in diabetes.

Han R, Huang H, Zhu J, Jin X, Wang Y, Xu Y Lipids Health Dis. 2024; 23(1):372.

PMID: 39538244 PMC: 11558907. DOI: 10.1186/s12944-024-02357-w.

Elevated meteorin-like protein from high-intensity interval training improves heart function via AMPK/HDAC4 pathway.

Wang Y, Yuan J, Liu H, Chen J, Zou J, Zeng X Genes Dis. 2024; 11(6):101100.

PMID: 39281832 PMC: 11400619. DOI: 10.1016/j.gendis.2023.101100.

Metrnl: a promising biomarker and therapeutic target for cardiovascular and metabolic diseases.

Dong W, Hu C, Hu M, Gao Y, Hu Y, Li K Cell Commun Signal. 2024; 22(1):389.

PMID: 39103830 PMC: 11301845. DOI: 10.1186/s12964-024-01767-8.

References

Dadmanesh M, Aghajani H, Fadaei R, Ghorban K . Lower serum levels of Meteorin-like/Subfatin in patients with coronary artery disease and type 2 diabetes mellitus are negatively associated with insulin resistance and inflammatory cytokines. PLoS One. 2018; 13(9):e0204180. PMC: 6136801. DOI: 10.1371/journal.pone.0204180. View

Heusch G, Musiolik J, Gedik N, Skyschally A . Mitochondrial STAT3 activation and cardioprotection by ischemic postconditioning in pigs with regional myocardial ischemia/reperfusion. Circ Res. 2011; 109(11):1302-8. DOI: 10.1161/CIRCRESAHA.111.255604. View

Beltran C, Pardo R, Bou-Teen D, Ruiz-Meana M, Villena J, Ferreira-Gonzalez I . Enhancing Glycolysis Protects against Ischemia-Reperfusion Injury by Reducing ROS Production. Metabolites. 2020; 10(4). PMC: 7240969. DOI: 10.3390/metabo10040132. View

Tabas I, Ron D . Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol. 2011; 13(3):184-90. PMC: 3107571. DOI: 10.1038/ncb0311-184. View

Omidkhoda N, Wallace Hayes A, Reiter R, Karimi G . The role of MicroRNAs on endoplasmic reticulum stress in myocardial ischemia and cardiac hypertrophy. Pharmacol Res. 2019; 150:104516. DOI: 10.1016/j.phrs.2019.104516. View

Jung T, Lee S, Kim H, Bang J, Abd El-Aty A, Hacimuftuoglu A . METRNL attenuates lipid-induced inflammation and insulin resistance via AMPK or PPARδ-dependent pathways in skeletal muscle of mice. Exp Mol Med. 2018; 50(9):1-11. PMC: 6137187. DOI: 10.1038/s12276-018-0147-5. View

Kerget B, Afsin D, Kerget F, Askin S, Akgun M . Is Metrnl an Adipokine İnvolved in the Anti-inflammatory Response to Acute Exacerbations of COPD?. Lung. 2020; 198(2):307-314. DOI: 10.1007/s00408-020-00327-4. View

Li S, Cao C, Chen H, Song J, Lee C, Zhang J . Atheroprotective effects of statins in patients with unstable angina by regulating the blood-borne microRNA network. Mol Med Rep. 2017; 16(1):817-827. PMC: 5482202. DOI: 10.3892/mmr.2017.6616. View

Yao Y, Lu Q, Hu Z, Yu Y, Chen Q, Wang Q . A non-canonical pathway regulates ER stress signaling and blocks ER stress-induced apoptosis and heart failure. Nat Commun. 2017; 8(1):133. PMC: 5527107. DOI: 10.1038/s41467-017-00171-w. View

10.

Gao L, Liu Y, Guo S, Yao R, Wu L, Xiao L . Circulating Long Noncoding RNA HOTAIR is an Essential Mediator of Acute Myocardial Infarction. Cell Physiol Biochem. 2017; 44(4):1497-1508. DOI: 10.1159/000485588. View

11.

Zhao X, Jia Y, Chen H, Yao H, Guo W . Plasma-derived exosomal miR-183 associates with protein kinase activity and may serve as a novel predictive biomarker of myocardial ischemic injury. Exp Ther Med. 2019; 18(1):179-187. PMC: 6566024. DOI: 10.3892/etm.2019.7555. View

12.

Mozaffarian D, Benjamin E, Go A, Arnett D, Blaha M, Cushman M . Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation. 2015; 133(4):e38-360. DOI: 10.1161/CIR.0000000000000350. View

13.

Benham A . Protein secretion and the endoplasmic reticulum. Cold Spring Harb Perspect Biol. 2012; 4(8):a012872. PMC: 3405867. DOI: 10.1101/cshperspect.a012872. View

14.

Kim S, Park J . Morin hydrate attenuates CSE-induced lipid accumulation, ER stress, and oxidative stress in RPE cells: implications for age-related macular degeneration. Free Radic Res. 2019; 53(8):865-874. DOI: 10.1080/10715762.2019.1637862. View

15.

Xu W, Yu H, Ma R, Ma L, Liu Q, Shan H . Apelin protects against myocardial ischemic injury by inhibiting dynamin-related protein 1. Oncotarget. 2017; 8(59):100034-100044. PMC: 5725000. DOI: 10.18632/oncotarget.21777. View

16.

Zhu S, Xu T, Luo Y, Zhang Y, Xuan H, Ma Y . Luteolin Enhances Sarcoplasmic Reticulum Ca2+-ATPase Activity through p38 MAPK Signaling thus Improving Rat Cardiac Function after Ischemia/Reperfusion. Cell Physiol Biochem. 2017; 41(3):999-1010. DOI: 10.1159/000460837. View

17.

Hou X, Fu M, Cheng B, Kang Y, Xie D . Galanthamine improves myocardial ischemia-reperfusion-induced cardiac dysfunction, endoplasmic reticulum stress-related apoptosis, and myocardial fibrosis by suppressing AMPK/Nrf2 pathway in rats. Ann Transl Med. 2020; 7(22):634. PMC: 6944599. DOI: 10.21037/atm.2019.10.108. View

18.

Wang S, Bian W, Zhen J, Zhao L, Chen W . Melatonin-Mediated Pak2 Activation Reduces Cardiomyocyte Death Through Suppressing Hypoxia Reoxygenation Injury-Induced Endoplasmic Reticulum Stress. J Cardiovasc Pharmacol. 2019; 74(1):20-29. DOI: 10.1097/FJC.0000000000000678. View

19.

Giustino G, Dangas G . Ischemia-reperfusion injury and ischemic post-conditioning in acute myocardial infarction: Lost in translation. Catheter Cardiovasc Interv. 2017; 90(7):1068-1069. DOI: 10.1002/ccd.27436. View

20.

Gao L, Chen H, Li C, Xiao Y, Yang D, Zhang M . ER stress activation impairs the expression of circadian clock and clock-controlled genes in NIH3T3 cells via an ATF4-dependent mechanism. Cell Signal. 2019; 57:89-101. DOI: 10.1016/j.cellsig.2019.01.008. View