LncRNA MIAT knockdown alleviates oxygen-glucose deprivation‑induced cardiomyocyte injury by regulating JAK2/STAT3 pathway via miR-181a-5p

Published:September 03, 2021DOI:https://doi.org/10.1016/j.jjcc.2021.08.018

      Highlights

      • 1
        Myocardial infarction-associated transcript (MIAT) was upregulated in oxygen-glucose deprivation (OGD)-induced cardiomyocytes.
      • 2
        MIAT silencing alleviated the injury of cardiomyocytes induced by OGD.
      • 3
        MIAT sponged miR-181a-5p to regulate the JAK2/STAT3 axis.
      • 4
        JAK2 overexpression or miR-181a-5p inhibition reversed the regulatory effects of MIAT silencing in OGD-induced cardiomyocyte damage.

      Abstract

      Background

      Coronary artery disease (CAD) is a common heart disease with high incidence and mortality. Myocardial ischemia is the main type of CAD, which negatively affects health worldwide. The aim of the present study was to investigate the function and mechanism of myocardial infarction-associated transcript (MIAT) in myocardial ischemia.

      Methods

      Human cardiomyocytes (HCM) were treated with oxygen-glucose deprivation (OGD) to set the in vitro model and mouse myocardial ischemia/reperfusion (I/R) was set for in vivo model. Cell viability and apoptosis were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay, flow cytometry, and immunofluorescence analysis. Inflammatory cytokines levels were detected by enzyme-linked immunosorbent assay. Gene and protein expressions were identified by quantitative real time-polymerase chain reaction or Western blotting. The interaction of MIAT, miR-181a-5p, and janus kinase 2 (JAK2) was identified by dual-luciferase report assay. Mouse heart tissues histopathological condition were observed by hematoxylin and eosin assays.

      Results

      Expression of MIAT and JAK2 were increased in OGD-treated HCM and mice of I/R model group, and miR-181a-5p was decreased. MIAT silencing could reverse the OGD treatment induced cell proliferation inhibition, cleaved caspase-3 and Bcl2-associated X (Bax) levels increased, while those of B-cell lymphoma-2 (Bcl-2) and mitochondria's cyt-C decreased. Besides, MIAT knockdown attenuated the OGD-induced increase of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 levels. Moreover, MIAT targeted miR-181a-5p to enhance the expression of JAK2 and signal Transducer and Activator of Transcription 3 (STAT3), and miR-181a-5p overexpression promoted proliferation, whereas it inhibited apoptosis in OGD-induced cardiomyocytes. Furthermore, the regulatory effects of MIAT knockdown in cell proliferation, apoptosis, and inflammatory injury was reversed by inhibition of miR-181a-5p or overexpression of JAK2 in OGD-treated HCM. Knockdown of MIAT reduced myocardial injury caused by I/R treatment in vivo.

      Conclusion

      MIAT knockdown inhibited apoptosis and inflammation by regulating JAK2/STAT3 signaling pathway via targeting miR-181a-5p in myocardial ischemia model. MIAT can be a possible therapeutic target for controlling the progression of myocardial ischemia.

      Graphical abstract

      Keywords

      To read this article in full you will need to make a payment
      Subscribe to Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Rymer J.A.
        • Rao S.V.
        Anemia and coronary artery disease–Pathophysiology, prognosis, and treatment.
        Coron Artery Dis. 2018; 29: 161-167
        • Khera A.V.
        • Kathiresan S.
        Genetics of coronary artery disease–Discovery, biology and clinical translation.
        Nat Rev Genet. 2017; 18: 331-344
        • Libby P.
        • Theroux P.
        Pathophysiology of coronary artery disease.
        Circ. 2005; 111: 3481-3488
        • Eskerud I.
        • Gerdts E.
        • Larsen T.H.
        • Lonnebakken M.T.
        Left ventricular hypertrophy contributes to myocardial ischemia in non-obstructive coronary artery disease (the MicroCAD study).
        Int J Cardiol. 2019; 286: 1-6
        • Neglia D.
        • Liga R.
        Myocardial ischemia without obstructive CAD–There is more than meets the eye!.
        J Nucl Cardiol. 2018; 25: 1770-1773
        • Yang X.
        • Zi X.H.
        LncRNA SNHG1 alleviates OGD induced injury in BMEC via miR-338/HIF-1alpha axis.
        Brain Res. 2019; 1714: 174-181
        • Richard J.L.C.
        • Eichhorn P.J.A.
        Platforms for investigating LncRNA functions.
        SLAS Technol. 2018; 23: 493-506
        • Bhan A.
        • Soleimani M.
        • Mandal S.S.
        Long noncoding RNA and cancer–A new paradigm.
        Cancer Res. 2017; 77: 3965-3981
        • Liu Y.
        • Yang Y.
        • Li L.
        • Liu Y.
        • Geng P.
        • Li G.
        • et al.
        LncRNA SNHG1 enhances cell proliferation, migration, and invasion in cervical cancer.
        Biochem Cell Biol. 2018; 96: 38-43
        • Hu Y.W.
        • Kang C.M.
        • Zhao J.J.
        • Nie Y.
        • Zheng L.
        • Li H.X.
        • et al.
        LncRNA PLAC2 down-regulates RPL36 expression and blocks cell cycle progression in glioma through a mechanism involving STAT1.
        J Cell Mol Med. 2018; 22: 497-510
        • Liang Y.P.
        • Liu Q.
        • Xu G.H.
        • Zhang J.
        • Chen Y.
        • Hua F.Z.
        • et al.
        The lncRNA ROR/miR-124-3p/TRAF6 axis regulated the ischaemia reperfusion injury-induced inflammatory response in human cardiac myocytes.
        J Bioenerg Biomembr. 2019; 51: 381-392
        • Wang K.
        • Liu C.Y.
        • Zhou L.Y.
        • Wang J.X.
        • Wang M.
        • Zhao B.
        • et al.
        APF lncRNA regulates autophagy and myocardial infarction by targeting miR-188-3p.
        Nat Commun. 2015; 6: 6779
        • Wang X.M.
        • Li X.M.
        • Song N.
        • Zhai H.
        • Gao X.M.
        • Yang Y.N.
        Long non-coding RNAs H19, MALAT1 and MIAT as potential novel biomarkers for diagnosis of acute myocardial infarction.
        Biomed Pharmacother. 2019; 118109208
        • Tan J.
        • Liu S.
        • Jiang Q.
        • Yu T.
        • Huang K.
        LncRNA-MIAT increased in patients with coronary atherosclerotic heart disease.
        Cardiol Res Pract. 2019; 20196280194
        • Zhou J.
        • Zhou Y.
        • Wang C.X.
        LncRNA-MIAT regulates fibrosis in hypertrophic cardiomyopathy (HCM) by mediating the expression of miR-29a-3p.
        J Cell Biochem. 2018; https://doi.org/10.1002/jcb.28001
        • Pizzini A.
        • Lunger L.
        • Sonnweber T.
        • Weiss G.
        • Tancevski I.
        The role of omega-3 fatty acids in the setting of coronary artery disease and COPD–A review.
        Nutr. 2018; 10: 1864
        • Ali M.
        • Girgis S.
        • Hassan A.
        • Rudick S.
        • Becker R.C.
        Inflammation and coronary artery disease: from pathophysiology to Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS).
        Coron Artery Dis. 2018; 29: 429-437
        • Tan H.
        • Qi J.
        • Fan B.Y.
        • Zhang J.
        • Su F.F.
        • Wang H.T.
        MicroRNA-24-3p attenuates myocardial ischemia/reperfusion injury by suppressing RIPK1 expression in mice.
        Cell Physiol Biochem. 2018; 51: 46-62
        • Wang J.
        • Chen W.
        • Lin H.
        • Zhang J.
        [Role of miRNA-340 in modulating gastric cancer cell proliferation and bioinformatic analysis].
        Nan Fang Yi Ke Da Xue Xue Bao. 2019; 39: 784-790
        • Di Leva G.
        • Garofalo M.
        • Croce C.M.
        MicroRNAs in cancer.
        Annu Rev Pathol. 2014; 9: 287-314
        • Martin E.C.
        • Qureshi A.T.
        • Llamas C.B.
        • Burow M.E.
        • King A.G.
        • Lee O.C.
        • et al.
        Mirna biogenesis pathway is differentially regulated during adipose derived stromal/stem cell differentiation.
        Adipocyte. 2018; 7: 96-105
        • Huang Z.Q.
        • Xu W.
        • Wu J.L.
        • Lu X.
        • Chen X.M.
        MicroRNA-374a protects against myocardial ischemia-reperfusion injury in mice by targeting the MAPK6 pathway.
        Life Sci. 2019; 232116619
        • Su Y.
        • Yuan J.
        • Zhang F.
        • Lei Q.
        • Zhang T.
        • Li K.
        • et al.
        MicroRNA-181a-5p and microRNA-181a-3p cooperatively restrict vascular inflammation and atherosclerosis.
        Cell Death Dis. 2019; 10: 365
        • Wang S.W.
        • Sun Y.M.
        The IL-6/JAK/STAT3 pathway–Potential therapeutic strategies in treating colorectal cancer (Review).
        Int J Oncol. 2014; 44: 1032-1040
        • Eskiler G.G.
        • Bezdegumeli E.
        • Ozman Z.
        • Ozkan A.D.
        • Bilir C.
        • Kucukakca B.N.
        • et al.
        IL-6 mediated JAK/STAT3 signaling pathway in cancer patients with cachexia.
        Bratisl Lek Listy. 2019; 66: 819-826
        • Alikhah A.
        • Pahlevan Kakhki M.
        • Ahmadi A.
        • Dehghanzad R.
        • Boroumand M.A.
        • Behmanesh M
        The role of lnc-DC long non-coding RNA and SOCS1 in the regulation of STAT3 in coronary artery disease and type 2 diabetes mellitus.
        J Diabetes Complications. 2018; 32: 258-265
        • Gao S.
        • Zhan L.
        • Yang Z.
        • Shi R.
        • Li H.
        • Xia Z.
        • et al.
        Remote limb ischaemic postconditioning protects against myocardial ischaemia/reperfusion injury in mice–Activation of JAK/STAT3-mediated Nrf2-antioxidant signalling.
        Cell Physiol Biochem. 2017; 43: 1140-1151
        • Zhou D.
        • Qu Z.
        • Wang H.
        • Su Y.
        • Wang Y.
        • Zhang W.
        • et al.
        The effect of hydroxy safflower yellow A on coronary heart disease through Bcl-2/Bax and PPAR-gamma.
        Exp Ther Med. 2018; 15: 520-526
        • Liu H.
        • Wang C.
        • Qiao Z.
        • Xu Y.
        Protective effect of curcumin against myocardium injury in ischemia reperfusion rats.
        Pharm Biol. 2017; 55: 1144-1148
        • Reichert K.
        • Colantuono B.
        • McCormack I.
        • Rodrigues F.
        • Pavlov V.
        • Abid M.R.
        Murine left anterior descending (LAD) coronary artery ligation: an improved and simplified model for myocardial infarction.
        J Vis Exp. 2017; 122: 55353
        • Pyxaras S.A.
        • Wijns W.
        • Reiber J.H.C.
        • Bax J.J.
        Invasive assessment of coronary artery disease.
        J Nucl Cardiol. 2018; 25: 860-871
        • Steg P.G.
        • Ducrocq G.
        Future of the prevention and treatment of coronary artery disease.
        Circ J. 2016; 80: 1067-1072
        • Wu Z.
        • Zhao S.
        • Li C.
        • Liu C.
        LncRNA TUG1 serves an important role in hypoxia-induced myocardial cell injury by regulating the miR1455pBinp3 axis.
        Mol Med Rep. 2018; 17: 2422-2430
        • Chen L.
        • Zhang D.
        • Yu L.
        • Dong H.
        Targeting MIAT reduces apoptosis of cardiomyocytes after ischemia/reperfusion injury.
        Bioengineered. 2019; 10: 121-132
        • Duan C.
        • Cao Z.
        • Tang F.
        • Jian Z.
        • Liang C.
        • Liu H.
        • et al.
        miRNA-mRNA crosstalk in myocardial ischemia induced by calcified aortic valve stenosis.
        Aging (Albany NY). 2019; 11: 448-466
        • Wang Z.
        • Wang Z.
        • Wang T.
        • Yuan J.
        • Wang X.
        • Zhang Z.
        Inhibition of miR-34a-5p protected myocardial ischemia reperfusion injury-induced apoptosis and reactive oxygen species accumulation through regulation of Notch Receptor 1 signaling.
        Rev Cardiovasc Med. 2019; 20: 187-197
        • Zou L.X.
        • Yu L.
        • Zhao X.M.
        • Liu J.
        • Lu H.G.
        • Liu G.W.
        • et al.
        MiR-375 mediates chondrocyte metabolism and oxidative stress in osteoarthritis mouse models through the JAK2/STAT3 signaling pathway.
        Cells Tissues Organs. 2019; 208: 13-24
        • Pan X.M.
        • He X.Y.
        • Yang Y.L.
        • Jia W.J.
        • Yang Z.Q.
        • Yan D.
        • et al.
        MiR-630 inhibits papillary thyroid carcinoma cell growth, metastasis, and epithelial-mesenchymal transition by suppressing JAK2/STAT3 signaling pathway.
        Eur Rev Med Pharmacol Sci. 2019; 23: 2453-2460
        • Jiang M.
        • Zhang W.
        • Zhang R.
        • Liu P.
        • Ye Y.
        • Yu W.
        • et al.
        Cancer exosome-derived miR-9 and miR-181a promote the development of early-stage MDSCs via interfering with SOCS3 and PIAS3 respectively in breast cancer.
        Oncogene. 2020; 39: 4681-4694
        • Cheng Y.
        • Li J.
        • Wang C.
        • Yang H.
        • Wang Y.
        • Zhan T.
        • et al.
        Inhibition of long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 attenuates high glucose-induced cardiomyocyte apoptosis via regulation of miR-181a-5p.
        Exp Anim. 2020; 69: 34-44
        • Paraskevopoulou M.D.
        • Hatzigeorgiou A.G.
        Analyzing MiRNA-LncRNA interactions.
        Methods Mol Biol. 2016; 1402: 271-286
        • Xuan Y.T.
        • Guo Y.
        • Han H.
        • Zhu Y.
        • Bolli R.
        An essential role of the JAK-STAT pathway in ischemic preconditioning.
        Proc Natl Acad Sci U S A. 2001; 98: 9050-9055
        • Billah M.
        • Ridiandries A.
        • Allahwala U.K.
        • Mudaliar H.
        • Dona A.
        • Hunyor S.
        • et al.
        Remote ischemic preconditioning induces cardioprotective autophagy and signals through the IL-6-dependent JAK-STAT pathway.
        Int J Mol Sci. 2020; 21: 1692
        • Perner F.
        • Perner C.
        • Ernst T.
        • Heidel F.H.
        Roles of JAK2 in aging, inflammation, hematopoiesis and malignant transformation.
        Cells. 2019; 8: 854
        • He L.
        • Du J.
        • Chen Y.
        • Liu C.
        • Zhou M.
        • Adhikari S.
        • et al.
        Renin-angiotensin system promotes colonic inflammation by inducing TH17 activation via JAK2/STAT pathway.
        Am J Physiol Gastrointest Liver Physiol. 2019; 316: G774-G784
        • Yu H.
        • Pardoll D.
        • Jove R.
        STATs in cancer inflammation and immunity–A leading role for STAT3.
        Nat Rev Cancer. 2009; 9: 798-809
        • Das A.
        • Salloum F.N.
        • Durrant D.
        • Ockaili R.
        • Kukreja R.C.
        Rapamycin protects against myocardial ischemia-reperfusion injury through JAK2-STAT3 signaling pathway.
        J Mol Cell Cardiol. 2012; 53: 858-869
        • Eid R.A.
        • Alkhateeb M.A.
        • Eleawa S.
        • Al-Hashem F.H.
        • Al-Shraim M.
        • El-Kott A.F.
        • et al.
        Cardioprotective effect of ghrelin against myocardial infarction-induced left ventricular injury via inhibition of SOCS3 and activation of JAK2/STAT3 signaling.
        Basic Res Cardiol. 2018; 113: 13
        • Li Z.Y.
        • Yang L.
        • Liu X.J.
        • Wang X.Z.
        • Pan Y.X.
        • Luo J.M.
        The long noncoding RNA MEG3 and its target miR-147 regulate JAK/STAT pathway in advanced chronic myeloid leukemia.
        EBioMedicine. 2018; 34: 61-75
        • Fan J.
        • Xu G.
        • Chang Z.
        • Zhu L.
        • Yao J.
        miR-210 transferred by lung cancer cell-derived exosomes may act as proangiogenic factor in cancer-associated fibroblasts by modulating JAK2/STAT3 pathway.
        Clin Sci (Lond). 2020; 134: 807-825