Plasma exosomal miR-142-3p induced by acupuncture protects against heart injury in rats with myocardial infarction by targeting Cofilin 2

Articles in Press

Document Type : Original Article

Authors

1 Department of Histoembryology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

2 Department of Chemistry, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

3 School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

4 Research Center for Health and Nutrition, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

5 Department of Anatomy, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

6 School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

10.22038/ijbms.2025.84835.18361

Abstract

Objective(s): The protective effects of acupuncture on myocardial injury have been identified in clinical trials. However, there is still a lack of comprehensive understanding of its fundamental mechanism. This research aimed to clarify the roles of plasma exosomes in the cardioprotection of acupuncture.
Materials and Methods: Myocardial infarcted rats were divided into control group, acupuncture group, and acupuncture plus GW4869 group. The rats without the performance of a myocardial infarction were divided into a sham group. Acupuncture was performed at bilateral PC6. 
Results: The results showed that the effects of acupuncture on increasing the thickness of the left ventricular infarct wall and inhibiting apoptosis of the damaged heart tissue were significantly reversed by GW4869. Among the five miRNAs of plasma exosomes increased by acupuncture, miR-142-3p was the unique miRNA up-regulated in myocardial tissue. Overexpressing miR-142-3p retarded oxidative damage of H9c2 by anti-apoptosis. miR-142-3p directly bound to and suppressed the expression of Cofilin 2 (CFL2). In vivo CFL2 expression was down-regulated by acupuncture and up-regulated by GW4869.
Conclusion: Our results suggest that plasma exosomes transfer cardio-protective signals of acupuncture to the injured heart and confer cardioprotective effects, and miR-142-3p emerges as a prominent exosomal miRNA in the inhibition of myocardial apoptosis by targeting CFL2.

Keywords

Main Subjects

References

1. Tan SCW, Zheng BB, Tang ML, Chu H, Zhao YT, Weng C. Global burden of cardiovascular diseases and its risk factors, 1990-2021: A systematic analysis for the global burden of disease study 2021. QJM 2025:hcaf022.
2. Tsao CW, Aday AW, Almarzooq ZI, Alonso A, Beaton AZ, Bittencourt MS, et al. Heart disease and stroke statistics-2022 update: A report from the american heart association. Circulation 2022; 145: e153-e639.
3. Gonuguntla K, Badu I, Duhan S, Sandhyavenu H, Chobufo MD, Taha A, et al. Sex and racial disparities in proportionate mortality of premature myocardial infarction in the United States: 1999 to 2020. J Am Heart Assoc 2024; 13: e033515-35527.
4. Hu SS. Epidemiology and current management of cardiovascular disease in China. J Geriatr Cardiol 2024; 21: 387-406.
5. Laflamme MA, Murry CE. Heart regeneration. Nature 2011; 473: 326-335.
6. Hadas Y, Vincek AS, Youssef E, Zak MM, Chepurko E, Sultana N, et al. Altering sphingolipid metabolism attenuates cell death and inflammatory response after myocardial infarction. Circulation 2020; 141: 916-930.
7. Heusch G, Rassaf T. Time to give up on cardioprotection? a critical appraisal of clinical studies on ischemic pre-, post-, and remote conditioning. Circ Res 2016; 119: 676-695.
8. Wang Q, Liang D, Wang F, Li W, Han Y, Zhang W, et al. Efficacy of electroacupuncture pretreatment for myocardial injury in patients undergoing percutaneous coronary intervention: A randomized clinical trial with a 2-year follow-up. Int J Cardiol 2015; 194: 28-35.
9. Mehta PK, Polk DM, Zhang X, Li N, Painovich J, Kothawade K, et al. A randomized controlled trial of acupuncture in stable ischemic heart disease patients. Int J Cardiol 2014; 176: 367-374.
10. Zhao TT, Liu JJ, Zhu J, Li H, Wang YC, Zhao Y, et al. SDF-1/CXCR4-mediated stem cell mobilization involved in cardioprotective effects of electroacupuncture on mouse with myocardial infarction. Oxid Med Cell Longev 2022; 2022: 4455183-4455199.
11. Ren Y, Chen Z, Wang R, Yu Y, Li D, He Y. Electroacupuncture improves myocardial ischemia injury via activation of adenosine receptors. Purinergic Signal 2020; 16: 337-345.
12. Wang C, Liang X, Yu Y, Li Y, Wen X, Liu M. Electroacupuncture pretreatment alleviates myocardial injury through regulating mitochondrial function. Eur J Med Res 2020; 25: 29-39.
13. Han YL, Chen S, Peng X. Electroacupuncture pretreatment at neiguan (PC6) attenuates autophagy in rats with myocardial ischemia reperfusion through the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway. J Tradit Chin Med 2021; 41: 455-462.
14. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science 2020; 367: eaau6977-7017.
15. Minghua W, Zhijian G, Chahua H, Qiang L, Minxuan X, Luqiao W, et al. Plasma exosomes induced by remote ischaemic preconditioning attenuate myocardial ischaemia/reperfusion injury by transferring miR-24. Cell Death Dis 2018; 9: 320-334.
16. Hou Z, Qin X, Hu Y, Zhang X, Li G, Wu J, et al. Longterm exercise-derived exosomal miR-342-5p: A novel exerkine for cardioprotection. Circ Res 2019; 124: 1386-1400.
17. Chen Y, Chen S, Zhang J, Hu X, Li N, Liu Z, et al. Electroacupuncture pre-treatment exerts a protective effect on LPS-induced cardiomyopathy in mice through the delivery of miR-381 via exosomes. Biochim Biophys Acta Mol Basis Dis 2024; 1870: 167208-167218.
18. Xu SY, Ni SM, Zeng CL, Peng YJ. Electro-acupuncture Promotes Angiogenesis via Exosomal miR-210 in the Hypoxia-induced HUVECs Mediated HIF-1alpha/VEGF/Notch 1 Signal Pathway. Curr Neurovasc Res 2022; 19: 406-417.
19. Wang QL, Wang HJ, Li ZH, Wang YL, Wu XP, Tan YZ. Mesenchymal stem cell-loaded cardiac patch promotes epicardial activation and repair of the infarcted myocardium. J Cell Mol Med 2017; 21: 1751-1766.
20. Yin CS, Jeong HS, Park HJ, Baik Y, Yoon MH, Choi CB, et al. A proposed transpositional acupoint system in a mouse and rat model. Res Vet Sci 2008; 84: 159-165.
21. Yang ZK, Wu ML, Xin JJ, He W, Su YS, Shi H, et al. Manual acupuncture and laser acupuncture for autonomic regulations in rats: Observation on heart rate variability and gastric motility. Evid Based Complement Alternat Med 2013; 2013: 276320-276327.
22. Coblentz PD, Ahn B, Hayward LF, Yoo JK, Christou DD, Ferreira LF. Small-hairpin RNA and pharmacological targeting of neutral sphingomyelinase prevent diaphragm weakness in rats with heart failure and reduced ejection fraction. Am J Physiol Lung Cell Mol Physiol 2019; 316: L679-L690.
23. Luo Y, Li WX, Zheng QS, Yan JQ, Yang YD, Shen SR, et al. OTUD1 deficiency attenuates myocardial ischemia/reperfusion induced cardiomyocyte apoptosis by regulating RACK1 phosphorylation. Acta Pharmacol Sin 2025. Online ahead of print.
DOI: 10.1038/s41401-025-01567-x. 
24. Li L, Cheng H, Zhou Y, Zhao D, Zhang X, Wang Y, et al. METTL3 regulates autophagy of hypoxia-induced cardiomyocytes by targeting ATG7. Cell Death Discov 2025; 11: 37-50.
25. Qian BJ, Tian CC, Ling XH, Yu LL, Ding FY, Huo JH, et al. miRNA-150-5p associate with antihypertensive effect of epigallocatechin-3-gallate revealed by aorta miRNome analysis of spontaneously hypertensive rat. Life Sci 2018; 203: 193-202.
26. Rider MA, Hurwitz SN, Meckes DG, Jr. ExtraPEG: A polyethylene glycol-based method for enrichment of extracellular vesicles. Sci Rep 2016; 6: 23978-23992.
27. Zou A, Xiao T, Chi B, Wang Y, Mao L, Cai D, et al. Engineered exosomes with growth differentiation factor-15 overexpression enhance cardiac repair after myocardial injury. Int J Nanomedicine 2024; 19: 3295-3314.
28. Meng WT, Zhu J, Wang YC, Shao CL, Li XY, Lu PP, et al. Targeting delivery of miR-146a via IMTP modified milk exosomes exerted cardioprotective effects by inhibiting NF-kappaB signaling pathway after myocardial ischemia-reperfusion injury. J Nanobiotechnology 2024; 22: 382-400.
29. Wan Z, Zhao L, Lu F, Gao X, Dong Y, Zhao Y, et al. Mononuclear phagocyte system blockade improves therapeutic exosome delivery to the myocardium. Theranostics 2020; 10: 218-230.
30. Bu T, Li Z, Hou Y, Sun W, Zhang R, Zhao L, et al. Exosome-mediated delivery of inflammation-responsive Il-10 mRNA for controlled atherosclerosis treatment. Theranostics 2021; 11: 9988-10000.
31. Qin HL, Han Y, Li JQ, Wu QH, Du YP, Li QH, et al. piRNA28846 has the potential to be a novel RNA nucleic acid drug for ovarian cancer. NPJ Precis Oncol 2025; 9: 65-80.
32. Yu Y, Su FF, Xu C. Maximakinin reversed H2O2 induced oxidative damage in rat cardiac H9c2 cells through AMPK/Akt and AMPK/ERK1/2 signaling pathways. Biomed Pharmacother 2024; 174: 116489-116500.
33. Wang N, Ma J, Ma Y, Lu L, Ma C, Qin P, et al. Electroacupuncture pretreatment mitigates myocardial ischemia/reperfusion injury via XBP1/GRP78/Akt pathway. Front Cardiovasc Med 2021; 8: 629547-629557.
34. Zhang T, Yang WX, Wang YL, Yuan J, Qian Y, Sun QM, et al. Electroacupuncture preconditioning attenuates acute myocardial ischemia injury through inhibiting NLRP3 inflammasome activation in mice. Life Sci 2020; 248: 117451.
35. Liu S, Chen X, Bao L, Liu T, Yuan P, Yang X, et al. Treatment of infarcted heart tissue via the capture and local delivery of circulating exosomes through antibody-conjugated magnetic nanoparticles. Nat Biomed Eng 2020; 4: 1063-1075.
36. Garcia-Martin R, Wang G, Brandao BB, Zanotto TM, Shah S, Kumar Patel S, et al. MicroRNA sequence codes for small extracellular vesicle release and cellular retention. Nature 2022; 601: 446-451.
37. Cheng M, Yang J, Zhao X, Zhang E, Zeng Q, Yu Y, et al. Circulating myocardial microRNAs from infarcted hearts are carried in exosomes and mobilise bone marrow progenitor cells. Nat Commun 2019; 10: 959-968.
38. Nian W, Fu C. Exosomes in myocardial infarction: Therapeutic potential and clinical application. J Cardiovasc Transl Res 2023; 16: 87-96.
39. Jung SE, Kim SW, Choi JW. Exploring cardiac exosomal RNAs of acute myocardial infarction. Biomedicines 2024; 12: 430-447.
40. Su Q, Lv X, Ye Z, Sun Y, Kong B, Qin Z, et al. The mechanism of miR-142-3p in coronary microembolization-induced myocardiac injury via regulating target gene IRAK-1. Cell Death Dis 2019; 10: 61.
41. Zhao Z, Qu F, Liu R, Xia Y. Differential expression of miR-142-3p protects cardiomyocytes from myocardial ischemia-reperfusion via TLR4/NFkB axis. J Cell Biochem 2020; 121: 3679-3690.
42. Subramanian K, Gianni D, Balla C, Assenza GE, Joshi M, Semigran MJ, et al. Cofilin-2 phosphorylation and sequestration in myocardial aggregates: novel pathogenetic mechanisms for idiopathic dilated cardiomyopathy. J Am Coll Cardiol 2015; 65: 1199-1214.
43. Chua BT, Volbracht C, Tan KO, Li R, Yu VC, Li P. Mitochondrial translocation of cofilin is an early step in apoptosis induction. Nat Cell Biol 2003; 5: 1083-1089.
44. Nguyen K, Chau VQ, Mauro AG, Durrant D, Toldo S, Abbate A, et al. Hydrogen sulfide therapy suppresses cofilin-2 and attenuates ischemic heart failure in a mouse model of myocardial infarction. J Cardiovasc Pharmacol Ther 2020; 25: 472-483.
45. Hu J, Zhang H, Li J, Jiang X, Zhang Y, Wu Q, et al. ROCK1 activation-mediated mitochondrial translocation of Drp1 and cofilin are required for arnidiol-induced mitochondrial fission and apoptosis. J Exp Clin Cancer Res 2020; 39: 37-53.
46. Su Q, Liu Y, Lv XW, Ye ZL, Sun YH, Kong BH, et al. Inhibition of lncRNA TUG1 up-regulates miR-142-3p to ameliorate myocardial injury during ischemia and reperfusion via targeting HMGB1- and Rac1-induced autophagy. J Mol Cell Cardiol 2019; 133: 12-25.
Iranian Journal of Basic Medical Sciences

Articles in Press, Accepted Manuscript
Available Online from 20 August 2025

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