miR-125b-5p alleviates the damage of myocardial infarction by inhibiting the NFAT2 to reduce F2RL2 expression
Abstract
Aim: To explore the effect of miR-125b-5p/nuclear factor of activated T cells 1 (NFAT2)/F2RL2 on myocardial infarction (MI). Method: After establishment of MI mouse model and oxygen glucose deprivation (OGD)-induced cell model, the effects of NFAT2 on the process of MI were observed, the effects of miR-125b-5p/NFAT2/F2RL2 on the cell viability, apoptosis, and inflammatory factors levels were determined. Result:NFAT2 silencing relieved MI and inhibited the inflammation in MI model mice. In OGD-induced human coronary artery endothelial cells and human cardiac microvascular endothelial cells, miR-125b-5p enhanced cell viability, yet repressed cell apoptosis and inflammatory factors and NFAT2 levels. NFAT2 overexpression reversed the effects of miR-125b-5p, while F2RL2 silencing offset the effects of NFAT2 overexpression. Conclusion: MiR-125b-5p alleviates MI injury by inhibiting NFAT2 level to reduce F2RL2 expression.
Plain language summary
This research proves that miR-125b-5p reduces the level of F2RL2 by preventing the activation of NFAT2 pathway, thereby reducing cardiogenic vascular endothelial cell damage and inflammation (heat, swelling and redness). This may provide a new treatment for heart attacks.
Graphical abstract
Papers of special note have been highlighted as: • of interest
References
- 1. . [Diagnosis and initial management of acute myocardial infarction]. MMW Fortschr Med. 161(4), 34–36 (2019).
- 2. . Acute Complications of Myocardial Infarction in the Current Era: Diagnosis and Management. J. Investig. Med. 63(7), 844–855 (2015).
- 3. . Cardiogenic Shock in the Setting of Acute Myocardial Infarction. Methodist Debakey Cardiovasc J. 16(1), 16–21 (2020).
- 4. . Management of cardiogenic shock complicating acute myocardial infarction: a review. Clin. Cardiol. 42(4), 484–493 (2019).
- 5. . Autophagy in vascular endothelial cells. Clin. Exp. Pharmacol. Physiol. 43(11), 1021–1028 (2016).
- 6. . Vascular Endothelial Cell Biology: An Update. Int J Mol Sci. 20(18), 4411 (2019).
- 7. . Endothelial Cell Calcium Signaling during Barrier Function and Inflammation. Am. J. Pathol. 190(3), 535–542 (2020).
- 8. Thrombin stimulates insulin secretion via protease-activated receptor-3. Islets. 7(4), e1118195 (2015).
- 9. PAR-3 controls endothelial planar polarity and vascular inflammation under laminar flow. EMBO Rep. 19(9), e45253 (2018).
- 10. . Protease-activated receptor signalling by coagulation proteases in endothelial cells. Thromb. Haemost. 112(5), 876–882 (2014).
- 11. . Up-regulation of tissue factor in human pulmonary artery endothelial cells after ultrafine particle exposure. Environ. Health Perspect. 115(4), 535–540 (2007).
- 12. Comprehensive Analyses of circRNA Expression Profiles and Function Prediction in Chicken Cecums After Eimeria tenella Infection. Front. Cell. Infect. Microbiol. 11,
doi: 10.3389/fcimb.2021.628667 (2021). - 13. lncRNA NEAT1 Downregulation Ameliorates the Myocardial Infarction of Mice by Regulating the miR-582-5p/F2RL2 Axis. Cardiovasc. Ther. 2022,
doi:: 10.1155/2022/4481360 (2022). • This paper describes the expression of F2RL2 in mice with myocardial infarction and serves as a reference for this study. - 14. Regulation of human vascular protease-activated receptor-3 through mRNA stabilization and the transcription factor nuclear factor of activated T cells (NFAT). Mol. Pharmacol. 80(2), 337–344 (2011). • This study shows that the expression of F2RL2 is regulated by the transcription factor NFAT2, and elaborated the relationship between F2RL2 and NFAT2.
- 15. . Decreased Expression of Cytotoxic T Lymphocyte-associated Protein 4: A Risk Factor of Myocardial Infarction. Iran J. Allergy Asthma Immunol. 21(1), 86–91 (2022).
- 16. Serum microRNA-499 and microRNA-208a as biomarkers of acute myocardial infarction. Int. J. Clin. Exp. Med. 7(1), 136–141 (2014).
- 17. . Molecular miR-19a in Acute Myocardial Infarction: Novel Potential Indicators of Prognosis and Early Diagnosis. Asian Pac. J. Cancer Prev. 21(4), 975–982 (2020).
- 18. . Up-Regulation of Cell-Free MicroRNA-1 and MicroRNA-221-3p Levels in Patients with Myocardial Infarction Undergoing Coronary Angiography. Adv Pharm Bull. 11(4), 719–727 (2021).
- 19. A carvedilol-responsive microRNA, miR-125b-5p protects the heart from acute myocardial infarction by repressing pro-apoptotic bak1 and klf13 in cardiomyocytes. J. Mol. Cell. Cardiol. 114, 72–82 (2018). • This study reports the effect of miR-125b-5p in myocardial infarction.
- 20. . Knockdown of lncRNA MALAT1 attenuates acute myocardial infarction through miR-320-Pten axis. Biomed. Pharmacother. 106, 738–746 (2018). • This is a reference for building animal models.
- 21. . miR-130 aggravates acute myocardial infarction-induced myocardial injury by targeting PPAR-γ. J. Cell. Biochem. 119(9), 7235–7244 (2018).
- 22. Quantification of Hantaan virus with a SYBR green I-based one-step qRT-PCR assay. PLOS ONE 8(11), e81525 (2013).
- 23. Aloe-emodin attenuates myocardial infarction and apoptosis via up-regulating miR-133 expression. Pharmacol. Res. 146,
doi: 10.1016/j.phrs.2019.104315 (2019). - 24. MicroRNA-449 and microRNA-34b/c function redundantly in murine testes by targeting E2F transcription factor-retinoblastoma protein (E2F-pRb) pathway. J. Biol. Chem. 287(26), 21686–21698 (2012).
- 25. . Endothelial cell barriers: transport of molecules between blood and tissues. Traffic. 20(6), 390–403 (2019).
- 26. . Downregulated miRNA-26a-5p induces the apoptosis of endothelial cells in coronary heart disease by inhibiting PI3K/AKT pathway. Eur. Rev. Med. Pharmacol. Sci. 23(11), 4940–4947 (2019).
- 27. . Coronary Artery Disease: From Mechanism to Clinical Practice. Adv. Exp. Med. Biol. 1177, 1–36 (2020).
- 28. . Identification of a putative regulator of early T cell activation genes. Science 241(4862), 202–205 (1988).
- 29. Activation of NFAT signaling establishes a tumorigenic microenvironment through cell autonomous and non-cell autonomous mechanisms. Oncogene 33(14), 1840–1849 (2014).
- 30. . NFAT control of immune function: New Frontiers for an Abiding Trooper. F1000Res. 7, 260 (2018).
- 31. Sanggenon C protects against pressure overload-induced cardiac hypertrophy via the calcineurin/NFAT2 pathway. Mol. Med. Rep. 16(4), 5338–5346 (2017).
- 32. . Doxorubicin-induces NFAT/Fas/FasL cardiac apoptosis in rats through activation of calcineurin and P38 MAPK and inhibition of mTOR signalling pathways. Clin. Exp. Pharmacol. Physiol. 47(4), 660–676 (2020).
- 33. . The biomarkers of key miRNAs and target genes associated with acute myocardial infarction. PeerJ. 8, e9129 (2020).
- 34. miR-125b-5p targeting TRAF6 relieves skeletal muscle atrophy induced by fasting or denervation. Ann. Transl. Med. 7(18), 456 (2019).
- 35. . MiR-125b-5p Inhibitor Might Protect Against Sevoflurane-induced Cognitive Impairments by Targeting LIMK1. Curr. Neurovasc. Res. 16(4), 382–391 (2019).
- 36. . Diagnostic value of miR-30d-5p and miR-125b-5p in acute myocardial infarction. Mol. Med. Rep. 14(1), 184–194 (2016).
- 37. Hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through miR-125b-mediated prevention of cell death in myocardial infarction. Theranostics 8(22), 6163–6177 (2018).
- 38. LncRNA MALAT1 prevents the protective effects of miR-125b-5p against acute myocardial infarction through positive regulation of NLRC5. Exp. Ther. Med. 19(2), 990–998 (2020).