MiR-21-5p-expressing bone marrow mesenchymal stem cells alleviate myocardial ischemia/reperfusion injury by regulating the circRNA_0031672/miR-21-5p/programmed cell death protein 4 pathway

Jing ZHANG; Chang-Jun LUO; Xiao-Qi XIONG; Jun LI; San-Hua TANG; Lin SUN; Qiang SU

doi:10.11909/j.issn.1671-5411.2021.12.004

Volume 18 Issue 12

Dec. 2021

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Article Navigation > Journal of Geriatric Cardiology > 2021 > 18(12): 1029-1043

Please cite this article as: ZHANG J, LUO CJ, XIONG XQ, LI J, TANG SH, SUN L, SU Q. MiR-21-5p-expressing bone marrow mesenchymal stem cells alleviate myocardial ischemia/reperfusion injury by regulating the circRNA_0031672/miR-21-5p/programmed cell death protein 4 pathway. J Geriatr Cardiol 2021; 18(12): 1029−1043. DOI: 10.11909/j.issn.1671-5411.2021.12.004

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Please cite this article as: ZHANG J, LUO CJ, XIONG XQ, LI J, TANG SH, SUN L, SU Q. MiR-21-5p-expressing bone marrow mesenchymal stem cells alleviate myocardial ischemia/reperfusion injury by regulating the circRNA_0031672/miR-21-5p/programmed cell death protein 4 pathway. J Geriatr Cardiol 2021; 18(12): 1029−1043. DOI: 10.11909/j.issn.1671-5411.2021.12.004

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MiR-21-5p-expressing bone marrow mesenchymal stem cells alleviate myocardial ischemia/reperfusion injury by regulating the circRNA_0031672/miR-21-5p/programmed cell death protein 4 pathway

doi: 10.11909/j.issn.1671-5411.2021.12.004

1.
Department of Cardiovascular Medicine, Liuzhou Municipal Liutie Central Hospital, Liuzhou, China
2.
Department of Clinical Laboratory, Liuzhou Municipal Liutie Central Hospital, Liuzhou, China
3.
Department of Cardiology, Affiliated Hospital of Guilin Medical University, Guangxi, China

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Corresponding author: suqiang1983@foxmail.com
Publish Date: 2021-12-28

Abstract

Abstract

BACKGROUND For patients with coronary heart disease, reperfusion treatment strategies are often complicated by ischemia/reperfusion (I/R) injury (IRI), leading to serious organ damage and malfunction. The miR-21/programmed cell death protein 4 (PDCD4) pathway is involved in the IRI of cardiomyocytes; however, the aberrant miR-21 expression remains unexplained. Therefore, this study aimed to explore whether circRNA_0031672 downregulates miR-21-5p expression during I/R and to determine whether miR-21-5p-expressing bone marrow mesenchymal stem cells (BMSCs) reduce myocardial IRI. METHODS CircRNA_0031672, miR-21-5p, and PDCD4 expressions were evaluated in the I/R rat model and hypoxia/re-oxygenation (H/R)-treated H9C2 cells. Their interactions were subsequently investigated using luciferase reporter and RNA pulldown assays. Methyltransferase-like 3, a methyltransferase catalyzing N6-methyladenosine (m6A), was overexpressed in H9C2 cells to determine whether m6A modification influences miR-21-5p targeting PDCD4. BMSCs stably expressing miR-21 were co-cultured with H9C2 cells to investigate the protective effect of BMSCs on H9C2 cells upon H/R. RESULTS I/R downregulated miR-21-5p expression and upregulated circRNA_0031672 and PDCD4 expressions. CircRNA_0031672 knockdown increased miR-21-5p expression, but repressed PDCD4 expression, indicating that circRNA_0031672 competitively bound to miR-21-5p and prevented it from targeting PDCD4 mRNA. The m6A modification regulated PDCD4 expression, but had no effect on miR-21-5p targeting PDCD4. The circRNA_0031672/miR-21-5p/PDCD4 axis regulated myocardial cells viability and apoptosis after H/R treatment; co-culture with miR-21-5p-expressing BMSCs restored miR-21-5p abundance in H9C2 cells and further reduced H9C2 cells apoptosis induced by H/R. CONCLUSIONS We identified a novel circRNA_0031672/miR-21-5p/PDCD4 signaling pathway that mediates the apoptosis of cardiomyocytes and successfully alleviates IRI in myocardial cells by co-culture with miR-21-5p-expressing BMSCs, offering novel insights into the IRI pathogenesis in cardiovascular diseases.

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References(42)

References

[1]	Ren J, Zhang Y. New therapetic approaches in the management of ischemia reperfusion injury and cardiometabolic diseases: opportunities and challenges. Curr Drug Targets 2017; 18: 1687−1688. doi: 10.2174/138945011815171019092703
[2]	Chang X, Lochner A, Wang HH, et al. Coronary microvascular injury in myocardial infarction: perception and knowledge for mitochondrial quality control. Theranostics 2021; 11: 6766−6785. doi: 10.7150/thno.60143
[3]	Wang J, Zhou H. Mitochondrial quality control mechanisms as molecular targets in cardiac ischemia-reperfusion injury. Acta Pharm Sin B 2020; 10: 1866−1879. doi: 10.1016/j.apsb.2020.03.004
[4]	Murphy E, Steenbergen C. Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev 2008; 88: 581−609. doi: 10.1152/physrev.00024.2007
[5]	Ma H, Guo R, Yu L, et al. Aldehyde dehydrogenase 2 (ALDH2) rescues myocardial ischaemia/reperfusion injury: role of autophagy paradox and toxic aldehyde. Eur Heart J 2011; 32: 1025−1038. doi: 10.1093/eurheartj/ehq253
[6]	Ye Y, Perez-Polo JR, Qian J, et al. The role of microRNA in modulating myocardial ischemia-reperfusion injury. Physiol Genomics 2011; 43: 534−542. doi: 10.1152/physiolgenomics.00130.2010
[7]	Su S, Luo D, Liu X, et al. MiR-494 up-regulates the PI3K/Akt pathway via targetting PTEN and attenuates hepatic ischemia/reperfusion injury in a rat model. Biosci Rep 2017; 37: BSR20170798. doi: 10.1042/BSR20170798
[8]	Liu Z, Jiang J, Yang Q, et al. MicroRNA-682-mediated downregulation of PTEN in intestinal epithelial cells ameliorates intestinal ischemia-reperfusion injury. Cell Death Dis 2016; 7: e2210. doi: 10.1038/cddis.2016.84
[9]	Memczak S, Jens M, Elefsinioti A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 2013; 495: 333−338. doi: 10.1038/nature11928
[10]	Tay Y, Rinn J, Pandolfi PP. The multilayered complexity of ceRNA crosstalk and competition. Nature 2014; 505: 344−352. doi: 10.1038/nature12986
[11]	Zhong Z, Huang M, Lv M, et al. Circular RNA MYLK as a competing endogenous RNA promotes bladder cancer progression through modulating VEGFA/VEGFR2 signaling pathway. Cancer Lett 2017; 403: 305−317. doi: 10.1016/j.canlet.2017.06.027
[12]	Xue J, Chen C, Luo F, et al. CircLRP6 regulation of ZEB1 via miR-455 is involved in the epithelial-mesenchymal transition during arsenite-induced malignant transformation of human keratinocytes. Toxicol Sci 2018; 162: 450−461. doi: 10.1093/toxsci/kfx269
[13]	Li J, Yang X, Qi Z, et al. The role of mRNA m6A methylation in the nervous system. Cell Biosci 2019; 9: 66. doi: 10.1186/s13578-019-0330-y
[14]	Wei CM, Gershowitz A, Moss B. Methylated nucleotides block 5’ terminus of HeLa cell messenger RNA. Cell 1975; 4: 379−386. doi: 10.1016/0092-8674(75)90158-0
[15]	Zhu ZM, Huo FC, Pei DS. Function and evolution of RNA N6-methyladenosine modification. Int J Biol Sci 2020; 16: 1929−1940. doi: 10.7150/ijbs.45231
[16]	Meyer KD, Saletore Y, Zumbo P, et al. Comprehensive analysis of mRNA methylation reveals enrichment in 3’ UTRs and near stop codons. Cell 2012; 149: 1635−1646. doi: 10.1016/j.cell.2012.05.003
[17]	Johnson J, Shojaee M, Mitchell Crow J, et al. From mesenchymal stromal cells to engineered extracellular vesicles: a new therapeutic paradigm. Front Cell Dev Biol 2021; 9: 705676. doi: 10.3389/fcell.2021.705676
[18]	Guo Y, Yu Y, Hu S, et al. The therapeutic potential of mesenchymal stem cells for cardiovascular diseases. Cell Death Dis 2020; 11: 349. doi: 10.1038/s41419-020-2542-9
[19]	Zomer HD, Vidane AS, Gonçalves NN, et al. Mesenchymal and induced pluripotent stem cells: general insights and clinical perspectives. Stem Cells Cloning 2015; 8: 125−134. doi: 10.2147/SCCAA.S88036
[20]	Gu H, Liu Z, Li Y, et al. Serum-derived extracellular vesicles protect against acute myocardial infarction by regulating miR-21/PDCD4 signaling pathway. Front Physiol 2018; 9: 348. doi: 10.3389/fphys.2018.00348
[21]	Li S, Fan Q, He S, et al. MicroRNA-21 negatively regulates Treg cells through a TGF-beta1/Smad-independent pathway in patients with coronary heart disease. Cell Physiol Biochem 2015; 37: 866−878. doi: 10.1159/000430214
[22]	Dong S, Cheng Y, Yang J, et al. MicroRNA expression signature and the role of microRNA-21 in the early phase of acute myocardial infarction. J Biol Chem 2009; 284: 29514−29525. doi: 10.1074/jbc.M109.027896
[23]	Jia Z, Lian W, Shi H, et al. Ischemic postconditioning protects against intestinal ischemia/reperfusion injury via the HIF-1alpha/miR-21 axis. Sci Rep 2017; 7: 16190. doi: 10.1038/s41598-017-16366-6
[24]	Shi H, Wang X, Lu Z, et al. YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA. Cell Res 2017; 27: 315−328. doi: 10.1038/cr.2017.15
[25]	Gilbert WV, Bell TA, Schaening C. Messenger RNA modifications: form, distribution, and function. Science 2016; 352: 1408−1412. doi: 10.1126/science.aad8711
[26]	Liu J, Yue Y, Han D, et al. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol 2014; 10: 93−95. doi: 10.1038/nchembio.1432
[27]	Li X, Wang X, Cheng Z, et al. AGO2 and its partners: a silencing complex, a chromatin modulator, and new features. Crit Rev Biochem Mol Biol 2020; 55: 33−53. doi: 10.1080/10409238.2020.1738331
[28]	Cao RY, Li Q, Miao Y, et al. The emerging role of microRNA-155 in cardiovascular diseases. Biomed Res Int 2016; 2016: 9869208. doi: 10.1155/2016/9869208
[29]	Gangwar RS, Rajagopalan S, Natarajan R, et al. Noncoding RNAs in cardiovascular disease: pathological relevance and emerging role as biomarkers and therapeutics. Am J Hypertens 2018; 31: 150−165. doi: 10.1093/ajh/hpx197
[30]	Lin L, Yang Z, Zheng G, et al. Analyses of changes in myocardial long non-coding RNA and mRNA profiles after severe hemorrhagic shock and resuscitation via RNA sequencing in a rat model. BMC Mol Biol 2018; 19: 11. doi: 10.1186/s12867-018-0113-8
[31]	Li H, Wu Y, Suo G, et al. Profiling neuron-autonomous lncRNA changes upon ischemia/reperfusion injury. Biochem Biophys Res Commun 2018; 495: 104−109. doi: 10.1016/j.bbrc.2017.10.157
[32]	Zhou J, Chen H, Fan Y. Systematic analysis of the expression profile of non-coding RNAs involved in ischemia/reperfusion-induced acute kidney injury in mice using RNA sequencing. Oncotarget 2017; 8: 100196−100215. doi: 10.18632/oncotarget.22130
[33]	Chen Z, Luo Y, Yang W, et al. Comparison analysis of dysregulated lncRNA profile in mouse plasma and liver after hepatic ischemia/reperfusion injury. PLoS One 2015; 10: e0133462. doi: 10.1371/journal.pone.0133462
[34]	Wang S, Chen J, Yu W, et al. Circular RNA DLGAP4 ameliorates cardiomyocyte apoptosis through regulating BCL2 via targeting miR-143 in myocardial ischemia-reperfusion injury. Int J Cardiol 2019; 279: 147. doi: 10.1016/j.ijcard.2018.09.023
[35]	Song YF, Zhao L, Wang BC, et al. The circular RNA TLK1 exacerbates myocardial ischemia/reperfusion injury via targeting miR-214/RIPK1 through TNF signaling pathway. Free Radic Biol Med 2020; 155: 69−80. doi: 10.1016/j.freeradbiomed.2020.05.013
[36]	Li M, Ding W, Tariq MA, et al. A circular transcript of ncx1 gene mediates ischemic myocardial injury by targeting miR-133a-3p. Theranostics 2018; 8: 5855−5869. doi: 10.7150/thno.27285
[37]	Chen L, Luo W, Zhang W, et al. CircDLPAG4/HECTD1 mediates ischaemia/reperfusion injury in endothelial cells via ER stress. RNA Biol 2020; 17: 240−253. doi: 10.1080/15476286.2019.1676114
[38]	Holly TA, Drincic A, Byun Y, et al. Caspase inhibition reduces myocyte cell death induced by myocardial ischemia and reperfusion in vivo. J Mol Cell Cardiol 1999; 31: 1709−1715. doi: 10.1006/jmcc.1999.1006
[39]	Yaoita H, Ogawa K, Maehara K, et al. Attenuation of ischemia/reperfusion injury in rats by a caspase inhibitor. Circulation 1998; 97: 276−281. doi: 10.1161/01.CIR.97.3.276
[40]	Xunian Z, Kalluri R. Biology and therapeutic potential of mesenchymal stem cell-derived exosomes. Cancer Sci 2020; 111: 3100−3110. doi: 10.1111/cas.14563
[41]	Moghaddam AS, Afshari JT, Esmaeili SA, et al. Cardioprotective microRNAs: lessons from stem cell-derived exosomal microRNAs to treat cardiovascular disease. Atherosclerosis 2019; 285: 1−9. doi: 10.1016/j.atherosclerosis.2019.03.016
[42]	Shao L, Zhang Y, Lan B, et al. MiRNA-sequence indicates that mesenchymal stem cells and exosomes have similar mechanism to enhance cardiac repair. Biomed Res Int 2017; 2017: 4150705. doi: 10.1155/2017/4150705