ISSN 1671-5411 CN 11-5329/R
Volume 18 Issue 12
Dec.  2021
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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
Citation: 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

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
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  •  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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  • [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
    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
    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
    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
    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
    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
    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
    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
    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
    Tay Y, Rinn J, Pandolfi PP. The multilayered complexity of ceRNA crosstalk and competition. Nature 2014; 505: 344−352. doi: 10.1038/nature12986
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    Gilbert WV, Bell TA, Schaening C. Messenger RNA modifications: form, distribution, and function. Science 2016; 352: 1408−1412. doi: 10.1126/science.aad8711
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
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