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Open Access 01-04-2022 | Myocardial Infarction

LncRNA HOTTIP Knockdown Attenuates Acute Myocardial Infarction via Regulating miR-92a-2/c-Met Axis

Authors: Beilei Wang, Likun Ma, Junyi Wang

Published in: Cardiovascular Toxicology | Issue 4/2022

Abstract

Increasing investigations have focused on long non-coding RNAs (lncRNAs) in various human diseases, including acute myocardial infarction (AMI). Although lncRNA HOTTIP has been identified to play an important role in coronary artery diseases, its role and specific mechanism in AMI remain unclear. To investigate the potential role of HOTTIP in MI, HOTTIP expression in hypoxia-treated cardiomyocytes and myocardial tissues of MI mice was evaluated. The potential targets of HOTTIP and miR-92a-2 were predicted using Starbase and Targetscan. To further determine the cardio-protective effects of HOTTIP in vivo, si-HOTTIP and miR-92a-2 mimics were individually or co-injected into mice through intramyocardial injection. Moreover, their roles were further confirmed in rescue experiments. HOTTIP was significantly upregulated in ischemic myocardium of MI mice and hypoxia-induced cardiomyocytes. Moreover, HOTTIP knockdown markedly promoted cardiomyocyte growth and inhibited cardiomyocyte apoptosis in vitro. Luciferase reporter assay showed that HOTTIP could directly sponge miR-92a-2 to negatively regulate miR-92a-2 expression. In addition, c-Met was identified as a direct target of miR-92a-2, and their correlation was confirmed by luciferase reporter assay. MiR-92a-2 overexpression significantly enhanced the protective effect of HOTTIP knockdown against AMI through partially inhibiting c-Met expression. Our results demonstrated that HOTTIP downregulation attenuated AMI progression via the targeting miR-92a-2/c-Met axis and suggested that HOTTIP might be a potential therapeutic target for AMI.

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Reed, G. W., Rossi, J. E., & Cannon, C. P. (2017). Acute myocardial infarction. Lancet (London, England), 389(10065), 197–210. https://doi.org/10.1016/s0140-6736(16)30677-8CrossRef

Pollard, T. J. (2000). The acute myocardial infarction. Primary Care, 27(3), 631–649. https://doi.org/10.1016/s0095-4543(05)70167-6CrossRefPubMed

Castro-Dominguez, Y., Dharmarajan, K., & McNamara, R. L. (2018). Predicting death after acute myocardial infarction. Trends in Cardiovascular Medicine, 28(2), 102–109. https://doi.org/10.1016/j.tcm.2017.07.011CrossRefPubMed

Mehta, L. S., Beckie, T. M., DeVon, H. A., Grines, C. L., Krumholz, H. M., Johnson, M. N., Lindley, K. J., Vaccarino, V., Wang, T. Y., Watson, K. E., & Wenger, N. K. (2016). Acute myocardial infarction in women: A scientific statement from the American Heart Association. Circulation, 133(9), 916–947. https://doi.org/10.1161/cir.0000000000000351CrossRefPubMed

Burgos, J. I., Morell, M., Mariángelo, J. I. E., & Vila Petroff, M. (2019). Hyperosmotic stress promotes endoplasmic reticulum stress-dependent apoptosis in adult rat cardiac myocytes. Apoptosis : an International Journal on Programmed Cell Death, 24(9–10), 785–797. https://doi.org/10.1007/s10495-019-01558-4CrossRef

Zhou, Y., Richards, A. M., & Wang, P. (2019). MicroRNA-221 Is Cardioprotective and Anti-fibrotic in a Rat Model of Myocardial Infarction. Molecular Therapy—Nucleic Acids, 17, 185–197. https://doi.org/10.1016/j.omtn.2019.05.018CrossRefPubMedPubMedCentral

Jarroux, J., Morillon, A., & Pinskaya, M. (2017). History, discovery, and classification of lncRNAs. Advances in Experimental Medicine and Biology, 1008, 1–46. https://doi.org/10.1007/978-981-10-5203-3_1CrossRefPubMed

Zhang, Y., Du, W., & Yang, B. (2019). Long non-coding RNAs as new regulators of cardiac electrophysiology and arrhythmias: Molecular mechanisms, therapeutic implications and challenges. Pharmacology & Therapeutics, 203, 107389. https://doi.org/10.1016/j.pharmthera.2019.06.011CrossRef

Wang, M., Jiang, S., Yu, F., Zhou, L., & Wang, K. (2019). Noncoding RNAs as Molecular Targets of Resveratrol Underlying Its Anticancer Effects. Journal of Agricultural and Food Chemistry, 67(17), 4709–4719. https://doi.org/10.1021/acs.jafc.9b01667CrossRefPubMed

10.

Tang, Y., & Ji, F. (2019). lncRNA HOTTIP facilitates osteosarcoma cell migration, invasion and epithelial-mesenchymal transition by forming a positive feedback loop with c-Myc. Oncology Letters, 18(2), 1649–1656. https://doi.org/10.3892/ol.2019.10463CrossRefPubMedPubMedCentral

11.

Rui, Y., Hu, M., Wang, P., Zhang, C., Xu, H., Li, Y., Zhang, Y., Gu, J., & Wang, Q. (2019). LncRNA HOTTIP mediated DKK1 downregulation confers metastasis and invasion in colorectal cancer cells. Histology and Histopathology, 34(6), 619–630. https://doi.org/10.14670/hh-18-043CrossRefPubMed

12.

Yuan, Q., Liu, Y., Fan, Y., Liu, Z., Wang, X., Jia, M., Geng, Z., Zhang, J., & Lu, X. (2018). LncRNA HOTTIP promotes papillary thyroid carcinoma cell proliferation, invasion and migration by regulating miR-637. The International Journal of Biochemistry & Cell Biology, 98, 1–9. https://doi.org/10.1016/j.biocel.2018.02.013CrossRef

13.

Liao, B., Chen, R., Lin, F., Mai, A., Chen, J., Li, H., Xu, Z., & Dong, S. (2018). Long noncoding RNA HOTTIP promotes endothelial cell proliferation and migration via activation of the Wnt/β-catenin pathway. Journal of Cellular Biochemistry, 119(3), 2797–2805. https://doi.org/10.1002/jcb.26448CrossRefPubMed

14.

Wang, Y., Li, G., Zhao, L., & Lv, J. (2018). Long noncoding RNA HOTTIP alleviates oxygen-glucose deprivation-induced neuronal injury via modulating miR-143/hexokinase 2 pathway. Journal of Cellular Biochemistry, 119(12), 10107–10117. https://doi.org/10.1002/jcb.27348CrossRefPubMed

15.

Fasolo, A., Sessa, C., Gianni, L., & Broggini, M. (2013). Seminars in clinical pharmacology: an introduction to MET inhibitors for the medical oncologist. Annals of Oncology : Official Journal of the European Society for Medical Oncology, 24(1), 14–20. https://doi.org/10.1093/annonc/mds520CrossRef

16.

Bahrami, A., Shahidsales, S., Khazaei, M., Ghayour-Mobarhan, M., Maftouh, M., Hassanian, S. M., & Avan, A. (2017). C-Met as a potential target for the treatment of gastrointestinal cancer: Current status and future perspectives. Journal of Cellular Physiology, 232(10), 2657–2673. https://doi.org/10.1002/jcp.25794CrossRefPubMed

17.

Lee, C., Whang, Y. M., Campbell, P., Mulcrone, P. L., Elefteriou, F., Cho, S. W., & Park, S. I. (2018). Dual targeting c-met and VEGFR2 in osteoblasts suppresses growth and osteolysis of prostate cancer bone metastasis. Cancer Letters, 414, 205–213. https://doi.org/10.1016/j.canlet.2017.11.016CrossRefPubMed

18.

Chen, R. L., Zhao, J., Zhang, X. C., Lou, N. N., Chen, H. J., Yang, X., Su, J., Xie, Z., Zhou, Q., Tu, H. Y., Zhong, W. Z., Yan, H. H., Guo, W. B., Wu, Y. L., & Yang, J. J. (2018). Crizotinib in advanced non-small-cell lung cancer with concomitant ALK rearrangement and c-Met overexpression. BMC Cancer, 18(1), 1171. https://doi.org/10.1186/s12885-018-5078-yCrossRefPubMedPubMedCentral

19.

Lee, S. J., Lee, J., Park, S. H., Park, J. O., Lim, H. Y., Kang, W. K., Park, Y. S., & Kim, S. T. (2018). c-MET overexpression in colorectal cancer: A poor prognostic factor for survival. Clinical Colorectal Cancer, 17(3), 165–169. https://doi.org/10.1016/j.clcc.2018.02.013CrossRefPubMed

20.

Liu, G., Hu, Y., Cheng, X., Wang, Y., Gu, Y., Liu, T., & Shi, H. (2019). Volumetric parameters on (18)F-FDG PET/CT predict the survival of patients with gastric cancer associated with their expression status of c-MET. BMC Cancer, 19(1), 790. https://doi.org/10.1186/s12885-019-5935-3CrossRefPubMedPubMedCentral

21.

Sato, T., Tani, Y., Murao, S., Fujieda, H., Sato, H., Matsumoto, M., Takeuchi, T., & Ohtsuki, Y. (2001). Focal enhancement of expression of c-Met/hepatocyte growth factor receptor in the myocardium in human myocardial infarction. Cardiovascular Pathology : The Official Journal of the Society for Cardiovascular Pathology, 10(5), 235–240. https://doi.org/10.1016/s1054-8807(01)00079-5CrossRef

22.

Gallo, S., Sala, V., Gatti, S., & Crepaldi, T. (2015). Cellular and molecular mechanisms of HGF/Met in the cardiovascular system. Clinical Science (London, England: 1979), 129(12), 1173–1193. https://doi.org/10.1042/cs20150502CrossRef

23.

Jiao, L., Li, M., Shao, Y., Zhang, Y., Gong, M., Yang, X., Wang, Y., Tan, Z., Sun, L., Xuan, L., Yu, Q., Li, Y., Gao, Y., Liu, H., Xu, H., Li, X., Zhang, Y., & Zhang, Y. (2019). lncRNA-ZFAS1 induces mitochondria-mediated apoptosis by causing cytosolic Ca(2+) overload in myocardial infarction mice model. Cell Death & Disease, 10(12), 942. https://doi.org/10.1038/s41419-019-2136-6CrossRef

24.

Hu, H., Wu, J., Yu, X., Zhou, J., Yu, H., & Ma, L. (2019). Long non-coding RNA MALAT1 enhances the apoptosis of cardiomyocytes through autophagy inhibition by regulating TSC2-mTOR signaling. Biological Research, 52(1), 58. https://doi.org/10.1186/s40659-019-0265-0CrossRefPubMedPubMedCentral

25.

Hu, H., Wu, J., Yu, X., Zhou, J., Yu, H., & Ma, L. (2020). Long noncoding RNA MALAT1 enhances the apoptosis of cardiomyocytes through autophagy modulation. Biochemistry and Cell Biology, 98, 1–7. https://doi.org/10.1139/bcb-2019-0062CrossRef

26.

Zhang, Z., Li, H., Chen, S., Li, Y., Cui, Z., & Ma, J. (2017). Knockdown of MicroRNA-122 Protects H9c2 Cardiomyocytes from Hypoxia-Induced Apoptosis and Promotes Autophagy. Medical Science Monitor : International Medical Journal of Experimental and Clinical Research, 23, 4284–4290. https://doi.org/10.12659/msm.902936CrossRef

27.

He, Q., Fang, Y., Lu, F., Pan, J., Wang, L., Gong, W., Fei, F., Cui, J., Zhong, J., Hu, R., Liang, M., Fang, L., Wang, H., Yu, M., & Zhang, Z.-F. (2019). Analysis of differential expression profile of miRNA in peripheral blood of patients with lung cancer. Journal of Clinical Laboratory Analysis. https://doi.org/10.1002/jcla.23003CrossRefPubMedPubMedCentral

28.

Liu, H., Li, G., Zhao, W., & Hu, Y. (2016). Inhibition of MiR-92a May Protect Endothelial Cells After Acute Myocardial Infarction in Rats: Role of KLF2/4. Medical Science Monitor : International Medical Journal of Experimental and Clinical Research, 22, 2451–2462. https://doi.org/10.12659/msm.897266CrossRef

29.

Fan, Y. Z., Huang, H., Wang, S., Tan, G. J., & Zhang, Q. Z. (2019). Effect of lncRNA MALAT1 on rats with myocardial infarction through regulating ERK/MAPK signaling pathway. European Review for Medical and Pharmacological Sciences, 23(20), 9041–9049. https://doi.org/10.26355/eurrev_201910_19306CrossRefPubMed

30.

Uchida, S., & Dimmeler, S. (2015). Long noncoding RNAs in cardiovascular diseases. Circulation Research, 116(4), 737–750. https://doi.org/10.1161/circresaha.116.302521CrossRefPubMed

31.

Yan, B., Yao, J., Liu, J. Y., Li, X. M., Wang, X. Q., Li, Y. J., Tao, Z. F., Song, Y. C., Chen, Q., & Jiang, Q. (2015). lncRNA-MIAT regulates microvascular dysfunction by functioning as a competing endogenous RNA. Circulation Research, 116(7), 1143–1156. https://doi.org/10.1161/circresaha.116.305510CrossRefPubMed

32.

Chen, L., Yang, W., Guo, Y., Chen, W., Zheng, P., Zeng, J., & Tong, W. (2017). Exosomal lncRNA GAS5 regulates the apoptosis of macrophages and vascular endothelial cells in atherosclerosis. PloS ONE, 12(9), e0185406. https://doi.org/10.1371/journal.pone.0185406CrossRefPubMedPubMedCentral

33.

Liu, Z., Liu, J., Wei, Y., Xu, J., Wang, Z., Wang, P., Sun, H., Song, Z., & Liu, Q. (2020). LncRNA MALAT1 prevents the protective effects of miR-125b-5p against acute myocardial infarction through positive regulation of NLRC5. Experimental and Therapeutic Medicine, 19(2), 990–998. https://doi.org/10.3892/etm.2019.8309CrossRefPubMed

34.

Ong, S. B., Katwadi, K., Kwek, X. Y., Ismail, N. I., Chinda, K., Ong, S. G., & Hausenloy, D. J. (2018). Non-coding RNAs as therapeutic targets for preventing myocardial ischemia-reperfusion injury. Expert Opinion on Therapeutic Targets, 22(3), 247–261. https://doi.org/10.1080/14728222.2018.1439015CrossRefPubMed

35.

Yang, J., Huang, X., Hu, F., Fu, X., Jiang, Z., & Chen, K. (2019). LncRNA ANRIL knockdown relieves myocardial cell apoptosis in acute myocardial infarction by regulating IL-33/ST2. Cell cycle (Georgetown, Tex), 18(23), 3393–3403. https://doi.org/10.1080/15384101.2019.1678965CrossRef

36.

Li, X., Zhou, J., & Huang, K. (2017). Inhibition of the lncRNA Mirt1 Attenuates Acute Myocardial Infarction by Suppressing NF-κB Activation. Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology, 42(3), 1153–1164. https://doi.org/10.1159/000478870CrossRef

37.

Li, T., Tian, H., Li, J., Zuo, A., Chen, J., Xu, D., Guo, Y., & Gao, H. (2019). Overexpression of lncRNA Gm2691 attenuates apoptosis and inflammatory response after myocardial infarction through PI3K/Akt signaling pathway. IUBMB Life, 71(10), 1561–1570. https://doi.org/10.1002/iub.2081CrossRefPubMed

38.

Su, Q., Liu, Y., Lv, X. W., Ye, Z. L., Sun, Y. H., Kong, B. H., & Qin, Z. B. (2019). Inhibition of lncRNA TUG1 upregulates miR-142–3p to ameliorate myocardial injury during ischemia and reperfusion via targeting HMGB1- and Rac1-induced autophagy. Journal of Molecular and Cellular Cardiology, 133, 12–25. https://doi.org/10.1016/j.yjmcc.2019.05.021CrossRefPubMed

39.

Liao, B., Dong, S., Xu, Z., Gao, F., Zhang, S., & Liang, R. (2020). LncRNA Kcnq1ot1 renders cardiomyocytes apoptosis in acute myocardial infarction model by up-regulating Tead1. Life Sciences, 256, 117811. https://doi.org/10.1016/j.lfs.2020.117811CrossRefPubMed

40.

Zhou, J., Li, D., Yang, B. P., & Cui, W. J. (2020). LncRNA XIST inhibits hypoxia-induced cardiomyocyte apoptosis via mediating miR-150–5p/Bax in acute myocardial infarction. European Review for Medical and Pharmacological Sciences, 24(3), 1357–1366. https://doi.org/10.26355/eurrev_202002_20193CrossRefPubMed

41.

Yang, G., & Lin, C. (2020). Long noncoding RNA SOX2-OT exacerbates hypoxia-induced cardiomyocytes injury by regulating miR-27a-3p/TGF β R1 axis. Cardiovascular Therapeutics, 2020, 1–11. https://doi.org/10.1155/2020/2016259CrossRef

42.

Teng, Y., Ding, M., Wang, X., Li, H., Guo, Q., Yan, J., & Gao, L. (2020). LncRNA RMRP accelerates hypoxia-induced injury by targeting miR-214–5p in H9c2 cells. Journal of Pharmacological Sciences, 142(2), 69–78. https://doi.org/10.1016/j.jphs.2019.07.014CrossRefPubMed

43.

Liang, H., Li, F., Li, H., Wang, R., & Du, M. (2021). Overexpression of lncRNA HULC attenuates myocardial ischemia/reperfusion injury in rat models and apoptosis of hypoxia/reoxygenation cardiomyocytes via targeting miR-377–5p through NLRP3/Caspase-1/IL-1β signaling pathway inhibition. Immunological Investigations, 50(8), 925–938. https://doi.org/10.1080/08820139.2020.1791178CrossRefPubMed

44.

Zhang, J., Gao, C., Meng, M., & Tang, H. (2016). Long noncoding RNA MHRT protects cardiomyocytes against H2O2-induced apoptosis. Biomolecules & Therapeutics, 24(1), 19–24. https://doi.org/10.4062/biomolther.2015.066CrossRef

45.

Han, F., Chen, Q., Su, J., Zheng, A., Chen, K., Sun, S., Wu, H., Jiang, L., Xu, X., Yang, M., Yang, F., Zhu, J., & Zhang, L. (2019). MicroRNA-124 regulates cardiomyocyte apoptosis and myocardial infarction through targeting Dhcr24. Journal of Molecular and Cellular Cardiology, 132, 178–188. https://doi.org/10.1016/j.yjmcc.2019.05.007CrossRefPubMed

46.

Guo, J., Liu, H. B., Sun, C., Yan, X. Q., Hu, J., Yu, J., Yuan, Y., & Du, Z. M. (2019). MicroRNA-155 Promotes Myocardial Infarction-Induced Apoptosis by Targeting RNA-Binding Protein QKI. Oxidative Medicine and Cellular Longevity, 2019, 4579806. https://doi.org/10.1155/2019/4579806CrossRefPubMedPubMedCentral

47.

Yin, Y., Lv, L., & Wang, W. (2019). Expression of miRNA-214 in the sera of elderly patients with acute myocardial infarction and its effect on cardiomyocyte apoptosis. Experimental and Therapeutic Medicine, 17(6), 4657–4662. https://doi.org/10.3892/etm.2019.7464CrossRefPubMedPubMedCentral

48.

Cheng, J., Wu, L. M., Deng, X. S., Wu, J., Lv, Z., Zhao, H. F., Yang, Z., & Ni, Y. (2018). MicroRNA-449a suppresses hepatocellular carcinoma cell growth via G1 phase arrest and the HGF/MET c-Met pathway. Hepatobiliary & Pancreatic Diseases International : HBPD INT, 17(4), 336–344. https://doi.org/10.1016/j.hbpd.2018.07.006CrossRef

49.

Xu, X., Zhu, Y., Liang, Z., Li, S., Xu, X., Wang, X., Wu, J., Hu, Z., Meng, S., Liu, B., Qin, J., Xie, L., & Zheng, X. (2016). c-Met and CREB1 are involved in miR-433-mediated inhibition of the epithelial-mesenchymal transition in bladder cancer by regulating Akt/GSK-3β/Snail signaling. Cell Death & Disease, 7(2), e2088. https://doi.org/10.1038/cddis.2015.274CrossRef

50.

Hoetelmans, R., van Slooten, H. J., Keijzer, R., Erkeland, S., van de Velde, C. J., & Dierendonck, J. H. (2000). Bcl-2 and Bax proteins are present in interphase nuclei of mammalian cells. Cell Death and Differentiation, 7(4), 384–392. https://doi.org/10.1038/sj.cdd.4400664CrossRefPubMed

Title: LncRNA HOTTIP Knockdown Attenuates Acute Myocardial Infarction via Regulating miR-92a-2/c-Met Axis
Authors: Beilei Wang
Likun Ma
Junyi Wang
Publication date: 01-04-2022
Publisher: Springer US
Keyword: Myocardial Infarction
Published in: Cardiovascular Toxicology / Issue 4/2022
Print ISSN: 1530-7905
Electronic ISSN: 1559-0259
DOI: https://doi.org/10.1007/s12012-021-09717-3

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