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miR-124-3p targeted SIRT1 to regulate cell apoptosis, inflammatory response, and oxidative stress in acute myocardial infarction in rats via modulation of the FGF21/CREB/PGC1α pathway

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Abstract

To investigate whether miR-124-3p influences cell apoptosis, inflammatory response, and oxidative stress in rats with acute myocardial infarction (AMI) by mediating the SIRT1/FGF21/CREB/PGC1α pathway. A dual-luciferase reporter gene assay was performed to verify the relationship between miR-124-3p and SIRT1. AMI rats were established via coronary artery ligation after injection with agomiR-124-3p, antagomiR-124-3p, and/or SIRT1 siRNA, and triphenyltetrazolium chloride (TTC), HE, and TUNEL stainings were performed. Bio-Plex rat cytokine assays were performed to determine proinflammatory factor levels. qRT-PCR and Western blotting were used to examine the mRNA and protein expression, respectively. The activity levels of antioxidant enzymes in myocardial tissues were also measured. miR-124-3p was confirmed to target SIRT1 in the H9C2 cells. AMI rats exhibited increased miR-124-3p expression and decreased SIRT1 expression in myocardial tissues. HE staining showed a disorganized cell arrangement and inflammatory cell infiltration in the myocardial tissues of the AMI rats, which was more severe in the rats injected with SIRT1 and agomiR-124-3p but was ameliorated in those treated with antagomiR-124-3p. Moreover, the AMI rats in the antagomiR-124-3p group presented with a reduction in infarct area with an increase in antioxidant enzyme activity, Bcl-2 expression, and activation of the FGF21/CREB/PGC1α pathway, as well as a decrease in cell apoptosis rate, Bax and Caspase-3 expression, and levels of proinflammatory factors, effects that were reversed by si-SIRT1. Inhibiting miR-124-3p expression may activate the FGF21/CREB/PGC1α pathway to reduce cell apoptosis, alleviate the inflammatory response, and attenuate oxidative stress in AMI rats by targeting SIRT1.

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References

  1. Aoi W (2014) Frontier impact of microRNAs in skeletal muscle research: a future perspective. Front Physiol 5:495

    PubMed  Google Scholar 

  2. Bao Q, Chen L, Li J, Zhao M, Wu S, Wu W, Liu X (2017) Role of microRNA-124 in cardiomyocyte hypertrophy inducedby angiotensin II. Cell Mol Biol (Noisy-le-grand) 63(4):23–27

    Article  CAS  Google Scholar 

  3. Brennan GP, Dey D, Chen Y, Patterson KP, Magnetta EJ, Hall AM, Dube CM, Mei YT, Baram TZ (2016) Dual and opposing roles of microRNA-124 in epilepsy are mediated through inflammatory and NRSF-dependent gene networks. Cell Rep 14(10):2402–2412

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Chen P, Pan J, Zhang X, Shi Z, Yang X (2018) The role of microRNA-181a in myocardial fibrosis following myocardial infarction in a rat model. Med Sci Monit 24:4121–4127

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Fu B, Zhang J, Zhang X, Zhang C, Li Y, Zhang Y, He T, Li P, Zhu X, Zhao Y, Zhang Y, Wang X (2014) Alpha-lipoic acid upregulates SIRT1-dependent PGC-1alpha expression and protects mouse brain against focal ischemia. Neuroscience. 281:251–257

    Article  PubMed  CAS  Google Scholar 

  6. Gacon J, Badacz R, Stepien E, Karch I, Enguita FJ, Zmudka K, Przewlocki T, Kablak-Ziembicka A (2018) Diagnostic and prognostic micro-RNAs in ischaemic stroke due to carotid artery stenosis and in acute coronary syndrome: a four-year prospective study. Kardiol Pol 76(2):362–369

    Article  PubMed  Google Scholar 

  7. Ghosh HS (2008) The anti-aging, metabolism potential of SIRT1. Curr Opin Investig Drugs 9(10):1095–1102

    PubMed  CAS  Google Scholar 

  8. Gilje P, Gidlof O, Rundgren M, Cronberg T, Al-Mashat M, Olde B, Friberg H, Erlinge D (2014) The brain-enriched microRNA miR-124 in plasma predicts neurological outcome after cardiac arrest. Crit Care 18(2):R40

    Article  PubMed  PubMed Central  Google Scholar 

  9. Gillum MP, Kotas ME, Erion DM, Kursawe R, Chatterjee P, Nead KT, Muise ES, Hsiao JJ, Frederick DW, Yonemitsu S, Banks AS, Qiang L, Bhanot S, Olefsky JM, Sears DD, Caprio S, Shulman GI (2011) SirT1 regulates adipose tissue inflammation. Diabetes. 60(12):3235–3245

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Guo ML, Guo LL, Weng YQ (2017) Implication of peripheral blood miRNA-124 in predicting acute myocardial infarction. Eur Rev Med Pharmacol Sci 21(5):1054–1059

    PubMed  Google Scholar 

  11. Han F, Chen Q, Su J, Zheng A, Chen K, Sun S, Wu H, Jiang L, Xu X, Yang M, Yang F, Zhu J, Zhang L (2019) MicroRNA-124 regulates cardiomyocyte apoptosis and myocardial infarction through targeting Dhcr24. J Mol Cell Cardiol 132:178–188

    Article  PubMed  CAS  Google Scholar 

  12. Hassan MQ, Akhtar MS, Akhtar M, Ali J, Haque SE, Najmi AK (2015) Edaravone protects rats against oxidative stress and apoptosis in experimentally induced myocardial infarction: biochemical and ultrastructural evidence. Redox Rep 20(6):275–281

    Article  PubMed  CAS  Google Scholar 

  13. He F, Liu H, Guo J, Yang D, Yu Y, Yu J, Yan X, Hu J, Du Z (2018) Inhibition of microRNA-124 reduces cardiomyocyte apoptosis following myocardial infarction via targeting STAT3. Cell Physiol Biochem 51(1):186–200

    Article  PubMed  CAS  Google Scholar 

  14. Hu MZ, Zhou B, Mao HY, Sheng Q, Du B, Chen JL, Pang QF, Ji Y (2016) Exogenous hydrogen sulfide postconditioning protects isolated rat hearts from ischemia/reperfusion injury through Sirt1/PGC-1α signaling pathway. Int Heart J 57(4):477–482

    Article  PubMed  CAS  Google Scholar 

  15. Huang W, Tian SS, Hang PZ, Sun C, Guo J, Du ZM (2016) Combination of microRNA-21 and microRNA-146a attenuates cardiac dysfunction and apoptosis during acute myocardial infarction in mice. Mol Ther Nucleic Acids 5:e296

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Khanna AK, Xu J, Mehra MR (2012) Antioxidant N-acetyl cysteine reverses cigarette smoke-induced myocardial infarction by inhibiting inflammation and oxidative stress in a rat model. Lab Investig 92(2):224–235

    Article  PubMed  CAS  Google Scholar 

  17. Kim EJ, Um SJ (2008) SIRT1: roles in aging and cancer. BMB Rep 41(11):751–756

    Article  PubMed  CAS  Google Scholar 

  18. Li B, Hu Y, Li X, Jin G, Chen X, Chen G, Chen Y, Huang S, Liao W, Liao Y, Teng Z, Bin J (2018) Sirt1 antisense long noncoding RNA promotes cardiomyocyte proliferation by enhancing the stability of Sirt1. J Am Heart Assoc 7(21):e009700

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Li Y, He XN, Li C, Gong L, Liu M (2019) Identification of candidate genes and microRNAs for acute myocardial infarction by weighted gene coexpression network analysis. Biomed Res Int 2019:5742608

    PubMed  PubMed Central  Google Scholar 

  20. Lin Z, Fang D (2013) The roles of SIRT1 in cancer. Genes Cancer 4(3-4):97–104

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Liu F, Hu H, Zhao J, Zhang Z, Ai X, Tang L, Xie L (2018) miR-124-3p acts as a potential marker and suppresses tumor growth in gastric cancer. Biomed Rep 9(2):147–155

    PubMed  PubMed Central  CAS  Google Scholar 

  22. Liu Y, Wang H, Wang X, Xie G (2019) MiR-29b inhibits ventricular remodeling by activating notch signaling pathway in the rat myocardial infarction model. Heart Surg Forum 22(1):E019–E023

    Article  PubMed  Google Scholar 

  23. Lu Y, Zhang Y, Shan H, Pan Z, Li X, Li B, Xu C, Zhang B, Zhang F, Dong D, Song W, Qiao G, Yang B (2009) MicroRNA-1 downregulation by propranolol in a rat model of myocardial infarction: a new mechanism for ischaemic cardioprotection. Cardiovasc Res 84(3):434–441

    Article  PubMed  CAS  Google Scholar 

  24. Lv Y, Chen S, Wu J, Lin R, Zhou L, Chen G, Chen H, Ke Y (2019) Upregulation of long non-coding RNA OGFRP1 facilitates endometrial cancer by regulating miR-124-3p/SIRT1 axis and by activating PI3K/AKT/GSK-3beta pathway. Artif Cells Nanomed Biotechnol 47(1):2083–2090

    Article  PubMed  CAS  Google Scholar 

  25. Nakamachi Y, Kawano S, Takenokuchi M, Nishimura K, Sakai Y, Chin T, Saura R, Kurosaka M, Kumagai S (2009) MicroRNA-124a is a key regulator of proliferation and monocyte chemoattractant protein 1 secretion in fibroblast-like synoviocytes from patients with rheumatoid arthritis. Arthritis Rheum 60(5):1294–1304

    Article  PubMed  Google Scholar 

  26. Park H, Ku SH, Park H, Hong J, Kim D, Choi BR, Pak HN, Lee MH, Mok H, Jeong JH, Choi D, Kim SH, Joung B (2015) RAGE siRNA-mediated gene silencing provides cardioprotection against ventricular arrhythmias in acute ischemia and reperfusion. J Control Release 217:315–326

    Article  PubMed  CAS  Google Scholar 

  27. Planavila A, Redondo-Angulo I, Villarroya F (2015) FGF21 and cardiac physiopathology. Front Endocrinol (Lausanne) 6:133

    Article  Google Scholar 

  28. Qiu R, Li W, Liu Y (2018) MicroRNA-204 protects H9C2 cells against hypoxia/reoxygenation-induced injury through regulating SIRT1-mediated autophagy. Biomed Pharmacother 100:15–19

    Article  PubMed  CAS  Google Scholar 

  29. Breivik H (2020) International Association for the Study of Pain: update on WHO-IASP activities. J Pain Symptom Manage 24(2):97–101

    Article  Google Scholar 

  30. Stachowiak EK, Fang X, Myers J, Dunham S, Stachowiak MK (2003) cAMP-induced differentiation of human neuronal progenitor cells is mediated by nuclear fibroblast growth factor receptor-1 (FGFR1). J Neurochem 84(6):1296–1312

    Article  PubMed  CAS  Google Scholar 

  31. Thackeray JT, Hupe HC, Wang Y, Bankstahl JP, Berding G, Ross TL, Bauersachs J, Wollert KC, Bengel FM (2018) Myocardial inflammation predicts remodeling and neuroinflammation after myocardial infarction. J Am Coll Cardiol 71(3):263–275

    Article  PubMed  CAS  Google Scholar 

  32. Ventura-Clapier R, Garnier A, Veksler V (2008) Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha. Cardiovasc Res 79(2):208–217

    Article  PubMed  CAS  Google Scholar 

  33. Wang D, Zhang H, Li M, Frid MG, Flockton AR, McKeon BA, Yeager ME, Fini MA, Morrell NW, Pullamsetti SS, Velegala S, Seeger W, McKinsey TA, Sucharov CC, Stenmark KR (2014) MicroRNA-124 controls the proliferative, migratory, and inflammatory phenotype of pulmonary vascular fibroblasts. Circ Res 114(1):67–78

    Article  PubMed  CAS  Google Scholar 

  34. Wang Y, Chen L, Wu Z, Wang M, Jin F, Wang N, Hu X, Liu Z, Zhang CY, Zen K, Chen J, Liang H, Zhang Y, Chen X (2016) miR-124-3p functions as a tumor suppressor in breast cancer by targeting CBL. BMC Cancer 16(1):826

    Article  PubMed  PubMed Central  Google Scholar 

  35. Xie J, Zhang X, Zhang L (2013) Negative regulation of inflammation by SIRT1. Pharmacol Res 67(1):60–67

    Article  PubMed  CAS  Google Scholar 

  36. Xu Y, Lai Y, Weng H, Tan L, Li Y, Chen G, Luo X, Ye Y (2019) MiR-124 sensitizes cisplatin-induced cytotoxicity against CD133(+) hepatocellular carcinoma cells by targeting SIRT1/ROS/JNK pathway. Aging (Albany NY) 11(9):2551–2564

    Article  CAS  Google Scholar 

  37. Yang W, Yi K, Yu H, Ding Y, Li D, Wei Y, You T, Xie X (2019) Correlation between pri-miR-124 (rs531564) polymorphism and congenital heart disease susceptibility in Chinese population at two different altitudes: a case-control and in silico study. Environ Sci Pollut Res Int 26(21):21983–21992

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Yao C, Shi X, Lin X, Shen L, Xu D, Feng Y (2015) Increased cardiac distribution of mono-PEGylated Radix Ophiopogonis polysaccharide in both myocardial infarction and ischemia/reperfusion rats. Int J Nanomedicine 10:409–418

    PubMed  PubMed Central  Google Scholar 

  39. Yao Y, Lu Q, Hu Z, Yu Y, Chen Q, Wang QK (2017) A non-canonical pathway regulates ER stress signaling and blocks ER stress-induced apoptosis and heart failure. Nat Commun 8(1):133

    Article  PubMed  PubMed Central  Google Scholar 

  40. Yu W, Peng W, Jiang H, Sha H, Li J (2017) LncRNA HOXA11-AS promotes proliferation and invasion by targeting miR-124 in human non-small cell lung cancer cells. Tumour Biol 39(10):1010428317721440

    Article  PubMed  Google Scholar 

  41. Yu LM, Dong X, Xue XD, Zhang J, Li Z, Wu HJ, Yang ZL, Yang Y, Wang HS (2019) Protection of the myocardium against ischemia/reperfusion injury by punicalagin through an SIRT1-NRF-2-HO-1-dependent mechanism. Chem Biol Interact 306:152–162

    Article  PubMed  CAS  Google Scholar 

  42. Zhou C, Cui Q, Su G, Guo X, Liu X, Zhang J (2016) MicroRNA-208b alleviates post-infarction myocardial fibrosis in a rat model by inhibiting GATA4. Med Sci Monit 22:1808–1816

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Zhu JN, Chen R, Fu YH, Lin QX, Huang S, Guo LL, Zhang MZ, Deng CY, Zou X, Zhong SL, Yang M, Zhuang J, Yu XY, Shan ZX (2013) Smad3 inactivation and miR-29b upregulation mediate the effect of carvedilol on attenuating the acute myocardium infarction-induced myocardial fibrosis in rat. PLoS One 8(9):e75557

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

We appreciate all the reviewers for their helpful suggestions in this work.

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Authors and Affiliations

  1. Department of Cardiology, Taihe Hospital, Hubei University of Medicine, Shiyan City, Hubei Province, China

    Yun-Jie Wei, Jun-Feng Wang, Fei Cheng, Hai-Jun Xu, Jia-Juan Chen & Jian Xiong

  2. Department of Neurology, Taihe Hospital, Hubei University of Medicine, No. 32, South Renmin Road, Shiyan City, 442000, Hubei Province, China

    Jing Wang

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Contributions

Yun-Jie Wei and Jun-Feng Wang conceived the idea and designed the study. Fei Cheng analyzed the data. Hai-Jun Xu designed illustrations and figures. Jia-Juan Chen conducted the experiments. Jian Xiong and Jing Wang wrote the manuscript, with all authors contributing to writing and providing feedback. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Jing Wang.

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Research involving human participants and/or animals

The research involves animals.

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The experimental animals were housed under the regulations of animal protection and use as described by the International Association for the Study of Pain (IASP), and this study received the approval of the Animal Ethics Committee of our hospital.

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Key Points

1. AMI rats exhibited increased miR-124-3p and decreased SIRT1 levels in myocardial tissues.

2. miR-124-3p downregulation activated the SIRT1/FGF21/CREB/PGC1α pathway.

3. Inhibiting miR-124-3p reduced the myocardial cell apoptosis rate and attenuated oxidative stress and the inflammatory response in AMI rats.

4. Inhibiting SIRT1 exacerbated the severity of AMI in rats.

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Wei, YJ., Wang, JF., Cheng, F. et al. miR-124-3p targeted SIRT1 to regulate cell apoptosis, inflammatory response, and oxidative stress in acute myocardial infarction in rats via modulation of the FGF21/CREB/PGC1α pathway. J Physiol Biochem 77, 577–587 (2021). https://doi.org/10.1007/s13105-021-00822-z

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  • DOI: https://doi.org/10.1007/s13105-021-00822-z

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