https://doi.org/10.4081/ejh.2022.3426
MALAT1 regulates hypertrophy of cardiomyocytes by modulating the miR-181a/HMGB2 pathway
Submitted: 20 April 2022
Accepted: 25 May 2022
Published: 21 June 2022
Accepted: 25 May 2022
Abstract Views: 1032
PDF: 587
HTML: 16
HTML: 16
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Noncoding RNAs are important for regulation of cardiac hypertrophy. The function of MALAT1 (a long noncoding mRNA), miR-181a, and HMGB2; their contribution to cardiac hypertrophy; and the regulatory relationship between them during this process remain unknown. In the present study, we treated primary cardiomyocytes with angiotensin II (Ang II) to mimic cardiac hypertrophy. MALAT1 expression was significantly downregulated in Ang II-treated cardiomyocytes compared with control cardiomyocytes. Ang II-induced cardiac hypertrophy was suppressed by overexpression of MALAT1 and promoted by genetic knockdown of MALAT1. A dual-luciferase reporter assay demonstrated that MALAT1 acted as a sponge for miR-181a and inhibited its expression during cardiac hypertrophy. Cardiac hypertrophy was suppressed by overexpression of a miR-181a inhibitor and enhanced by overexpression of a miR-181a mimic. HMGB2 was downregulated during cardiac hypertrophy and was identified as a target of miR-181a by bioinformatics analysis and a dual-luciferase reporter assay. miR-181a overexpression decreased the mRNA and protein levels of HMGB2. Rescue experiments indicated that MALAT1 overexpression reversed the effect of miR-181a on HMGB2 expression. In summary, the results of the present study show that MALAT1 acts as a sponge for miR-181a and thereby regulates expression of HMGB2 and development of cardiac hypertrophy. The novel MALAT1/miR-181a/HMGB2 axis might play a crucial role in cardiac hypertrophy and serve as a new therapeutic target.
Yurista SR, Chong CR, Badimon JJ, Kelly DP, de Boer RA, Westenbrink BD. Therapeutic potential of ketone bodies for patients with cardiovascular disease: JACC state-of-the-art review. J Am Coll Cardiol 2021;77:1660-9.
DOI: https://doi.org/10.1016/j.jacc.2020.12.065
Tada H, Fujino N, Hayashi K, Kawashiri MA, Takamura M. Human genetics and its impact on cardiovascular disease. J Cardiol 2022;79:233-9.
DOI: https://doi.org/10.1016/j.jjcc.2021.09.005
Zhang Y, Xin L, Xiang M, Shang C, Wang Y, Wang Y, et al. The molecular mechanisms of ferroptosis and its role in cardiovascular disease. Biomed Pharmacother 2022;145:112423.
DOI: https://doi.org/10.1016/j.biopha.2021.112423
Mishra S, Kass DA. Cellular and molecular pathobiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 2021;18:735.
DOI: https://doi.org/10.1038/s41569-021-00516-5
Lei H, Hu J, Sun K, Xu D. The role and molecular mechanism of epigenetics in cardiac hypertrophy. Heart Fail Rev 2021;26:1505-14.
DOI: https://doi.org/10.1007/s10741-020-09959-3
Ramachandra CJA, Cong S, Chan X, Yap EP, Yu F, Hausenloy DJ. Oxidative stress in cardiac hypertrophy: From molecular mechanisms to novel therapeutic targets. Free Radic Biol Med 2021;166:297-312.
DOI: https://doi.org/10.1016/j.freeradbiomed.2021.02.040
Liu CF, Tang WHW. Epigenetics in Cardiac hypertrophy and heart failure. JACC Basic Transl Sci 2019;4:976-93.
DOI: https://doi.org/10.1016/j.jacbts.2019.05.011
Zhu L, Li C, Liu Q, Xu W, Zhou X. Molecular biomarkers in cardiac hypertrophy. J Cell Mol Med 2019;23:1671-7.
DOI: https://doi.org/10.1111/jcmm.14129
He J, Luo Y, Song J, Tan T, Zhu H. Non-coding RNAs and pathological cardiac hypertrophy. Adv Exp Med Biol 2020;1229:231-45.
DOI: https://doi.org/10.1007/978-981-15-1671-9_13
Qiu GZ, Tian W, Fu HT, Li CP, Liu B. Long noncoding RNA-MEG3 is involved in diabetes mellitus-related microvascular dysfunction. Biochem Biophys Res Commun 2016;471:135-41.
DOI: https://doi.org/10.1016/j.bbrc.2016.01.164
Li Y, Liang Y, Zhu Y, Zhang Y, Bei Y. Noncoding RNAs in cardiac hypertrophy. J Cardiovasc Transl Res 2018;11:439-49.
DOI: https://doi.org/10.1007/s12265-018-9797-x
Greco CM, Condorelli G. Epigenetic modifications and noncoding RNAs in cardiac hypertrophy and failure. Nat Rev Cardiol 2015;12:488-97.
DOI: https://doi.org/10.1038/nrcardio.2015.71
Sun J, Wang C. Long non-coding RNAs in cardiac hypertrophy. Heart Fail Rev 2020;25:1037-45.
DOI: https://doi.org/10.1007/s10741-019-09882-2
Zhang J, Feng C, Song C, Ai B, Bai X, Liu Y, et al. Identification and analysis of a key long non-coding RNAs (lncRNAs)-associated module reveal functional lncRNAs in cardiac hypertrophy. J Cell Mol Med 2018;22:892-903.
DOI: https://doi.org/10.1111/jcmm.13376
Michalik KM, You X, Manavski Y, Doddaballapur A, Zornig M, Braun T, et al. Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth. Circ Res 2014;114:1389-97.
DOI: https://doi.org/10.1161/CIRCRESAHA.114.303265
Scolari FL, Faganello LS, Garbin HI, Piva EMB, Biolo A. A systematic review of microRNAs in patients with hypertrophic cardiomyopathy. Int J Cardiol 2021;327:146-54.
DOI: https://doi.org/10.1016/j.ijcard.2020.11.004
Gebert LFR, MacRae IJ. Regulation of microRNA function in animals. Nat Rev Mol Cell Biol 2019;20:21-37.
DOI: https://doi.org/10.1038/s41580-018-0045-7
Mens MMJ, Ghanbari M. Cell cycle regulation of stem cells by MicroRNAs. Stem Cell Rev Rep 2018;14:309-22.
DOI: https://doi.org/10.1007/s12015-018-9808-y
Wang Y, Blelloch R. Cell cycle regulation by MicroRNAs in embryonic stem cells. Cancer Res 2009;69:4093-6.
DOI: https://doi.org/10.1158/0008-5472.CAN-09-0309
Fazmin IT, Achercouk Z, Edling CE, Said A, Jeevaratnam K. Circulating microRNA as a biomarker for coronary artery disease. Biomolecules 2020;10:1354.
DOI: https://doi.org/10.3390/biom10101354
Omidkhoda N, Wallace Hayes A, Reiter RJ, Karimi G. The role of MicroRNAs on endoplasmic reticulum stress in myocardial ischemia and cardiac hypertrophy. Pharmacol Res 2019;150:104516.
DOI: https://doi.org/10.1016/j.phrs.2019.104516
Ooi JY, Bernardo BC, McMullen JR. The therapeutic potential of miRNAs regulated in settings of physiological cardiac hypertrophy. Future Med Chem 2014;6:205-22.
DOI: https://doi.org/10.4155/fmc.13.196
Li AL, Lv JB, Gao L. MiR-181a mediates Ang II-induced myocardial hypertrophy by mediating autophagy. Eur Rev Med Pharmacol Sci 2017;21:5462-70.
Garg A, Foinquinos A, Jung M, Janssen-Peters H, Biss S, Bauersachs J, et al. MiRNA-181a is a novel regulator of aldosterone-mineralocorticoid receptor-mediated cardiac remodelling. Eur J Heart Fail 2020;22:1366-77.
DOI: https://doi.org/10.1002/ejhf.1813
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.
DOI: https://doi.org/10.1538/expanim.19-0058
Niu L, Yang W, Duan L, Wang X, Li Y, Xu C, et al. Biological functions and theranostic potential of HMGB family members in human cancers. Ther Adv Med Oncol 2020;12:1758835920970850.
DOI: https://doi.org/10.1177/1758835920970850
Stros M, Ozaki T, Bacikova A, Kageyama H, Nakagawara A. HMGB1 and HMGB2 cell-specifically down-regulate the p53- and p73-dependent sequence-specific transactivation from the human Bax gene promoter. J Biol Chem 2002;277:7157-64.
DOI: https://doi.org/10.1074/jbc.M110233200
Taniguchi N, Carames B, Kawakami Y, Amendt BA, Komiya S, Lotz M. Chromatin protein HMGB2 regulates articular cartilage surface maintenance via beta-catenin pathway. Proc Natl Acad Sci U S A 2009;106:16817-22.
DOI: https://doi.org/10.1073/pnas.0904414106
Laurent B, Randrianarison-Huetz V, Marechal V, Mayeux P, Dusanter-Fourt I, Dumenil D. High-mobility group protein HMGB2 regulates human erythroid differentiation through trans-activation of GFI1B transcription. Blood 2010;115:687-95.
DOI: https://doi.org/10.1182/blood-2009-06-230094
Ronfani L, Ferraguti M, Croci L, Ovitt CE, Scholer HR, Consalez GG, et al. Reduced fertility and spermatogenesis defects in mice lacking chromosomal protein Hmgb2. Development 2001;128:1265-73.
DOI: https://doi.org/10.1242/dev.128.8.1265
Zhou X, Li M, Huang H, Chen K, Yuan Z, Zhang Y, et al. HMGB2 regulates satellite-cell-mediated skeletal muscle regeneration through IGF2BP2. J Cell Sci 2016;129:4305-16.
DOI: https://doi.org/10.1242/jcs.189944
Franklin S, Chen H, Mitchell-Jordan S, Ren S, Wang Y, Vondriska TM. Quantitative analysis of the chromatin proteome in disease reveals remodeling principles and identifies high mobility group protein B2 as a regulator of hypertrophic growth. Mol Cell Proteomics 2012;11:M111.014258.
Monte E, Rosa-Garrido M, Karbassi E, Chen H, Lopez R, Rau CD, et al. reciprocal regulation of the cardiac epigenome by chromatin structural proteins Hmgb and Ctcf: Implications for transcriptional regulation. J Biol Chem 2016;291:15428-46.
DOI: https://doi.org/10.1074/jbc.M116.719633
Nie X, Fan J, Li H, Yin Z, Zhao Y, Dai B, et al. miR-217 promotes cardiac hypertrophy and dysfunction by targeting PTEN. Mol Ther Nucleic Acids 2018;12:254-66.
DOI: https://doi.org/10.1016/j.omtn.2018.05.013
Gao Y, Zhao D, Xie WZ, Meng T, Xu C, Liu Y, et al. Rap1GAP mediates angiotensin II-induced cardiomyocyte hypertrophy by inhibiting autophagy and increasing oxidative stress. Oxid Med Cell Longev 2021;2021:7848027.
DOI: https://doi.org/10.1155/2021/7848027
Poltronieri C, Maccatrozzo L, Simontacchi C, Bertotto D, Funkenstein B, Patruno M, et al. Quantitative RT-PCR analysis and immunohistochemical localization of HSP70 in sea bass Dicentrarchus labrax exposed to transport stress. Eur J Histochem 2007;51:125-35.
Fede C, Albertin G, Petrelli L, Sfriso MM, Biz C, De Caro R, et al. Expression of the endocannabinoid receptors in human fascial tissue. Eur J Histochem 2016;60:2643.
DOI: https://doi.org/10.4081/ejh.2016.2643
Liu Z, Liu J, Wei Y, Xu J, Wang Z, Wang P, et al. LncRNA MALAT1 prevents the protective effects of miR-125b-5p against acute myocardial infarction through positive regulation of NLRC5. Exp Ther Med 2020;19:990-8.
DOI: https://doi.org/10.3892/etm.2019.8309
Zhao H, Zhang X, Zheng Y, Li Y, Wang X, Hu N, et al. Propofol protects rat cardiomyocytes from anthracycline-induced apoptosis by regulating microRNA-181a in vitro and in vivo. Oxid Med Cell Longev 2018;2018:2109216.
DOI: https://doi.org/10.1155/2018/2109216
Jiang C, Liu F, Xiao S, He L, Wu W, Zhao Q. miR-29a-3p enhances the radiosensitivity of oral squamous cell carcinoma cells by inhibiting ADAM12. Eur J Histochem 2021;65:3295.
DOI: https://doi.org/10.4081/ejh.2021.3295
Liu J, Niu Z, Zhang R, Peng Z, Wang L, Liu Z, et al. MALAT1 shuttled by extracellular vesicles promotes M1 polarization of macrophages to induce acute pancreatitis via miR-181a-5p/HMGB1 axis. J Cell Mol Med 2021;25:9241-54.
DOI: https://doi.org/10.1111/jcmm.16844
Wang Y, Mou Q, Zhu Z, Zhao L, Zhu L. MALAT1 promotes liver fibrosis by sponging miR181a and activating TLR4NFkappaB signaling. Int J Mol Med 2021;48:215.
DOI: https://doi.org/10.3892/ijmm.2021.5048
Sun Y, Jiang T, Jia Y, Zou J, Wang X, Gu W. LncRNA MALAT1/miR-181a-5p affects the proliferation and adhesion of myeloma cells via regulation of Hippo-YAP signaling pathway. Cell Cycle 2019;18:2509-23.
DOI: https://doi.org/10.1080/15384101.2019.1652034
Lu Z, Luo T, Pang T, Du Z, Yin X, Cui H, et al. MALAT1 promotes gastric adenocarcinoma through the MALAT1/miR-181a-5p/AKT3 axis. Open Biol 2019;9:190095.
DOI: https://doi.org/10.1098/rsob.190095
Puthanveetil P, Gutschner T, Lorenzen J. MALAT1: a therapeutic candidate for a broad spectrum of vascular and cardiorenal complications. Hypertens Res 2020;43:372-9.
DOI: https://doi.org/10.1038/s41440-019-0378-4
Zhang X, Li DY, Reilly MP. Long intergenic noncoding RNAs in cardiovascular diseases: Challenges and strategies for physiological studies and translation. Atherosclerosis 2019;281:180-8.
DOI: https://doi.org/10.1016/j.atherosclerosis.2018.09.040
Tripathi V, Shen Z, Chakraborty A, Giri S, Freier SM, Wu X, et al. Long noncoding RNA MALAT1 controls cell cycle progression by regulating the expression of oncogenic transcription factor B-MYB. PLoS Genet 2013;9:e1003368.
DOI: https://doi.org/10.1371/journal.pgen.1003368
Peters T, Hermans-Beijnsberger S, Beqqali A, Bitsch N, Nakagawa S, Prasanth KV, et al. Long non-coding RNA Malat-1 is dispensable during pressure overload-induced cardiac remodeling and failure in mice. PLoS One 2016;11:e0150236.
DOI: https://doi.org/10.1371/journal.pone.0150236
Wang C, Liu G, Yang H, Guo S, Wang H, Dong Z, et al. MALAT1-mediated recruitment of the histone methyltransferase EZH2 to the microRNA-22 promoter leads to cardiomyocyte apoptosis in diabetic cardiomyopathy. Sci Total Environ 2021;766:142191.
DOI: https://doi.org/10.1016/j.scitotenv.2020.142191
Song J, He Q, Guo X, Wang L, Wang J, Cui C, et al. Mesenchymal stem cell-conditioned medium alleviates high fat-induced hyperglucagonemia via miR-181a-5p and its target PTEN/AKT signaling. Mol Cell Endocrinol 2021;537:111445.
DOI: https://doi.org/10.1016/j.mce.2021.111445
Vaskova E, Ikeda G, Tada Y, Wahlquist C, Mercola M, Yang PC. Sacubitril/valsartan improves cardiac function and decreases myocardial fibrosis via downregulation of exosomal miR-181a in a rodent chronic myocardial infarction model. J Am Heart Assoc 2020;9:e015640.
DOI: https://doi.org/10.1161/JAHA.119.015640
Raut SK, Singh GB, Rastogi B, Saikia UN, Mittal A, Dogra N, et al. miR-30c and miR-181a synergistically modulate p53-p21 pathway in diabetes induced cardiac hypertrophy. Mol Cell Biochem 2016;417:191-203.
DOI: https://doi.org/10.1007/s11010-016-2729-7
Calogero S, Grassi F, Aguzzi A, Voigtländer T, Ferrier P, Ferrari S, et al. The lack of chromosomal protein Hmg1 does not disrupt cell growth but causes lethal hypoglycaemia in newborn mice. Nat Genet 1999;22:276-80.
DOI: https://doi.org/10.1038/10338
Zhang L, Liu M, Jiang H, Yu Y, Yu P, Tong R, et al. Extracellular high-mobility group box 1 mediates pressure overload-induced cardiac hypertrophy and heart failure. J Cell Mol Med 2016;20:459-70.
DOI: https://doi.org/10.1111/jcmm.12743
Jia Z, Xue R, Liu G, Li L, Yang J, Pi G, et al. HMGB1 Is involved in the protective effect of the PPAR alpha agonist fenofibrate against cardiac hypertrophy. PPAR Res 2014;2014:541394.
DOI: https://doi.org/10.1155/2014/541394
Funayama A, Shishido T, Netsu S, Narumi T, Kadowaki S, Takahashi H, et al. Cardiac nuclear high mobility group box 1 prevents the development of cardiac hypertrophy and heart failure. Cardiovasc Res 2013;99:657-64.
DOI: https://doi.org/10.1093/cvr/cvt128
Franklin S, Chen HD, Mitchell-Jordan S, Ren SX, Wang YB, Vondriska TM. Quantitative analysis of the chromatin proteome in disease reveals remodeling principles and identifies high mobility group protein B2 as a regulator of hypertrophic growth. Mol Cell Proteomics 2012;11:12.
DOI: https://doi.org/10.1074/mcp.M111.014258
Sato M, Miyata K, Tian Z, Kadomatsu T, Ujihara Y, Morinaga J, et al. Loss of endogenous HMGB2 promotes cardiac dysfunction and pressure overload-induced heart failure in mice. Circ J 2019;83:368-78.
DOI: https://doi.org/10.1253/circj.CJ-18-0925
Ethics Approval
All animal procedures were approved by the Animal Research Committee of Ganzhou People’s Hospital (approval No. SJTY(E) 2018-067)Rights
Science and Technology Project of Jiangxi Province (No. 20203BBGL73188) -- Natural Science Foundation of Jiangxi, China (No. 20212ACB206031)How to Cite
Chen, F. ., Li, W. ., Zhang, D. ., Fu, Y. ., Yuan, W. ., Luo, G. ., … Luo, J. (2022). MALAT1 regulates hypertrophy of cardiomyocytes by modulating the miR-181a/HMGB2 pathway. European Journal of Histochemistry, 66(3). https://doi.org/10.4081/ejh.2022.3426
Copyright (c) 2022 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.
Similar Articles
- A. Rus, M.L. Del Moral, F. Molina, M.A. Peinado, Upregulation of cardiac NO/NOS system during short-term hypoxia and the subsequent reoxygenation period , European Journal of Histochemistry: Vol. 55 No. 2 (2011)
- ChenHui Zhu, LiJuan Lin, ChangQing Huang, ZhiHui Wu, Activation of Hedgehog pathway by circEEF2/miR-625-5p/TRPM2 axis promotes prostate cancer cell proliferation through mitochondrial stress , European Journal of Histochemistry: Vol. 68 No. 4 (2024)
- V. Di Felice, G. Zummo, Stem cell populations in the heart and the role of Isl1 positive cells , European Journal of Histochemistry: Vol. 57 No. 2 (2013)
- V. Insolia, V.M. Piccolini, Brain morphological defects in prolidase deficient mice: first report , European Journal of Histochemistry: Vol. 58 No. 3 (2014)
- Kazuhiko Hashimoto, Yutaka Oda, Fumihisa Nakamura, Ryosuke Kakinoki, Masao Akagi, Lectin-like, oxidized low-density lipoprotein receptor-1-deficient mice show resistance to age-related knee osteoarthritis , European Journal of Histochemistry: Vol. 61 No. 1 (2017)
- C. Serradifalco, P. Catanese, L. Rizzuto, F. Cappello, R. Puleio, V. Barresi, C. M. Nunnari, G. Zummo, V. Di Felice, Embryonic and foetal Islet-1 positive cells in human hearts are also positive to c-Kit , European Journal of Histochemistry: Vol. 55 No. 4 (2011)
- R Bugorsky, JC Perriard, G Vassalli, Genetic selection system allowing monitoring of myofibrillogenesis in living cardiomyocytes derived from mouse embryonic stem cells , European Journal of Histochemistry: Vol. 52 No. 1 (2008)
- Liying Shen, Kongjie Lu, Zhenfeng Chen, Yingwei Zhu, Cong Zhang, Li Zhang, Pre-treatment with galectin-1 attenuates lipopolysaccharide-induced myocarditis by regulating the Nrf2 pathway , European Journal of Histochemistry: Vol. 67 No. 4 (2023)
- T. Kocsis, J. Baán, G. Müller, L. Mendler, L. Dux, A. Keller-Pintér, Skeletal muscle cellularity and glycogen distribution in the hypermuscular Compact mice , European Journal of Histochemistry: Vol. 58 No. 3 (2014)
- Giulia Ronchi, Pierluigi Tos, Elia Angelino, Luisa Muratori, Simone Reano, Nicoletta Filigheddu, Andrea Graziani, Stefano Geuna, Stefania Raimondo, Effect of unacylated ghrelin on peripheral nerve regeneration , European Journal of Histochemistry: Vol. 65 No. s1 (2021): Special Collection on Advances in Neuromorphology in Health and Disease
You may also start an advanced similarity search for this article.
