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MALAT1 affects hypoxia-induced vascular endothelial cell injury and autophagy by regulating miR-19b-3p/HIF-1α axis

Abstract

Cardiovascular disease has become the leading cause of death in the world. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays an important role in cardiovascular disease, such as stroke. However, the role of MALAT1 in hypoxia (HYP)-induced vascular endothelial cells (VECs) remains unclear. In the present study, HYP-treated human umbilical vein endothelial cells (HUVECs) were utilized to simulate HYP-induced VEC injury. It was found that after HYP treatment, the levels of MALAT1 and hypoxia-induced factor-1 (HIF-1α) in HUVECs were upregulated, while the level of miR-19b-3p was downregulated. Knockdown of MALAT1 with siRNA significantly reduced the HIF-1α level induced by HYP. In addition, MALAT1 knockdown inhibited HYP-induced HUVECs apoptosis, autophagy and inflammation. The overexpression of HIF-1α overcame the effect of MALAT1 knockdown. Mechanism analysis showed that MALAT1-targeted miR-19b-3p and then regulated downstream HIF-1α. MALAT1 knockdown increased the level of miR-19b-3p in cells, and increased miR-19b-3p further inhibited the expression of HIF-1α, thereby reducing the HYP-induced HUVECs apoptosis, autophagy and inflammation. Taken together, these results suggest that MALAT1 may be a potential target for mitigating HYP-induced endothelial cell injury.

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References

  1. 1.

    Li B, Xu X, Wang X, Yu H, Li X, Tao W, Wang Y, Yang L (2012) A systems biology approach to understanding the mechanisms of action of chinese herbs for treatment of cardiovascular disease. Int J Mol Sci 13(10):13501–13520. https://doi.org/10.3390/ijms131013501

  2. 2.

    Cao H, Yu D, Yan X, Wang B, Yu Z, Song Y, Sheng L (2019) Hypoxia destroys the microstructure of microtubules and causes dysfunction of endothelial cells via the PI3K/Stathmin1 pathway. Cell Biosci 9(1):20. https://doi.org/10.1186/s13578-019-0283-1

  3. 3.

    Lin L, Li G, Zhang W, Wang YL, Yang H (2019) Low-dose aspirin reduces hypoxia-induced sFlt1 release via the JNK/AP-1 pathway in human trophoblast and endothelial cells. J Cell Physiol 234:18928–18941. https://doi.org/10.1002/jcp.28533

  4. 4.

    Cui C, Li Y, Liu Y (2019) Down-regulation of miR-377 suppresses high glucose and hypoxia-induced angiogenesis and inflammation in human retinal endothelial cells by direct up-regulation of target gene SIRT1. Hum Cell 32:260–274. https://doi.org/10.1007/s13577-019-00240-w

  5. 5.

    Wang HW, Jiang X, Zhang Y, Wang J, Xie J, Wang YQ, Li YH (2019) FGF21 protects against hypoxia injury through inducing HSP72 in cerebral microvascular endothelial cells. Front Pharmacol 10:101. https://doi.org/10.3389/fphar.2019.00101

  6. 6.

    Luo J, Martinez J, Yin X, Sanchez A, Tripathy D, Grammas P (2012) Hypoxia induces angiogenic factors in brain microvascular endothelial cells. Microvasc Res 83:138–145. https://doi.org/10.1016/j.mvr.2011.11.004

  7. 7.

    Jessica C, Lounsbury KM (2015) Hypoxia-mediated biological control. J Cell Biochem 112:735–744. https://doi.org/10.1002/jcb.22956

  8. 8.

    Wei H, Hu J, Pu J, Tang Q, Li W, Ma R, Xu Z, Tan C, Yao T, Wu X, Long X, Wang J (2019) Long noncoding RNA HAGLROS promotes cell proliferation, inhibits apoptosis and enhances autophagy via regulating miR-5095/ATG12 axis in hepatocellular carcinoma cells. Int Immunopharmacol 73:72–80. https://doi.org/10.1016/j.intimp.2019.04.049

  9. 9.

    Wan P, Su W, Zhang Y, Li Z, Deng C, Li J, Jiang N, Huang S, Long E, Zhuo Y (2019) LncRNA H19 initiates microglial pyroptosis and neuronal death in retinal ischemia/reperfusion injury. Cell Death Differ. https://doi.org/10.1038/s41418-019-0351-4

  10. 10.

    Sun R, Zhang L (2019) Long non-coding RNA MALAT1 regulates cardiomyocytes apoptosis after hypoxia/reperfusion injury via modulating miR-200a-3p/PDCD4 axis. Biomed Pharmacother 111:1036–1045. https://doi.org/10.1016/j.biopha.2018.12.122

  11. 11.

    Ruan W, Li J, Xu Y, Wang Y, Zhao F, Yang X, Jiang H, Zhang L, Saavedra JM, Shi L, Pang T (2019) MALAT1 up-regulator polydatin protects brain microvascular integrity and imeliorates stroke through C/EBPbeta/MALAT1/CREB/PGC-1alpha/PPARgamma pathway. Cell Mol Neurobiol 39:265–286. https://doi.org/10.1007/s10571-018-00646-4

  12. 12.

    Michalik KM, Xintian Y, Yosif M, Anuradha D, Martin ZR, Thomas B, David J, Yuliya P, Wei C, Shizuka U (2014) Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth. Circ Res 114:1389–1397. https://doi.org/10.1161/CIRCRESAHA.114.303265

  13. 13.

    Song Y, Yang L, Guo R, Lu N, Shi Y, Wang X (2019) Long noncoding RNA MALAT1 promotes high glucose-induced human endothelial cells pyroptosis by affecting NLRP3 expression through competitively binding miR-22. Biochem Biophys Res Commun 509:359–366. https://doi.org/10.1016/j.bbrc.2018.12.139

  14. 14.

    Huang XJ, Xia Y, He GF, Zheng LL, Cai YP, Yin Y, Wu Q (2018) MALAT1 promotes angiogenesis of breast cancer. Oncol Rep 40:2683–2689. https://doi.org/10.3892/or.2018.6705

  15. 15.

    Ren L, Wei C, Li K, Lu Z (2019) LncRNA MALAT1 up-regulates VEGF-A and ANGPT2 to promote angiogenesis in brain microvascular endothelial cells against oxygen-glucose deprivation via targetting miR-145. Biosci Rep 39(3):BSR20180226. https://doi.org/10.1042/bsr20180226

  16. 16.

    Wang K, Yang C, Shi J, Gao T (2019) Ox-LDL-induced lncRNA MALAT1 promotes autophagy in human umbilical vein endothelial cells by sponging miR-216a-5p and regulating Beclin-1 expression. Eur J Pharmacol 858:172338. https://doi.org/10.1016/j.ejphar.2019.04.019

  17. 17.

    Puthanveetil P, Chen S, Feng B, Gautam A, Chakrabarti S (2015) Long non-coding RNA MALAT1 regulates hyperglycaemia induced inflammatory process in the endothelial cells. J Cell Mol Med 19:1418–1425. https://doi.org/10.1111/jcmm.12576

  18. 18.

    Wang L, Yang G, Zhao D, Wang J, Bai Y, Peng Q, Wang H, Fang R, Chen G, Wang Z, Wang K, Li G, Yang Y, Wang Z, Guo P, Peng L, Hou D, Xu W (2019) CD103-positive CSC exosome promotes EMT of clear cell renal cell carcinoma: role of remote MiR-19b-3p. Mol Cancer 18(1):86. https://doi.org/10.1186/s12943-019-0997-z

  19. 19.

    Wei YP, Wang XH, Liu G, Zhang JF, Yang YX, Zhang J, Song XL, Li ZD, Zhao LD (2018) Matrine exerts inhibitory effects in melanoma through the regulation of miR-19b-3p/PTEN. Int J Oncol 53:791–800. https://doi.org/10.3892/ijo.2018.4414

  20. 20.

    Bulgakova O, Zhabayeva D, Kussainova A, Pulliero A, Izzotti A, Bersimbaev R (2018) miR-19 in blood plasma reflects lung cancer occurrence but is not specifically associated with radon exposure. Oncol Lett 15:8816–8824. https://doi.org/10.3892/ol.2018.8392

  21. 21.

    Maleki E, Ghaedi K, Shahanipoor K, Karimi Kurdistani Z (2018) Down-regulation of microRNA-19b in hormone receptor-positive/HER2-negative breast cancer. APMIS 126:303–308. https://doi.org/10.1111/apm.12820

  22. 22.

    Chen X, Qu Y, Cheng Y, Wang J, Lei X, Song G, Zhang H, Wang H, Lei F (2018) MiR-19b-3p regulates MAPK1 expression in embryonic fibroblasts from the great tit (Parus major) under hypoxic conditions. Cell Physiol Biochem 46:546–560. https://doi.org/10.1159/000488621

  23. 23.

    Jing L, Shao J, Sun W, Lan T, Jia Z, Ma H, Wang H (2019) Protective effects of two novel nitronyl nitroxide radicals on heart failure induced by hypobaric hypoxia. Life Sci. https://doi.org/10.1016/j.lfs.2019.05.037

  24. 24.

    Byun Y, Choi YC, Jeong Y, Lee G, Yoon S, Jeong Y, Yoon J, Baek K (2019) MiR-200c downregulates HIF-1alpha and inhibits migration of lung cancer cells. Cell Mol Biol Lett 24:28. https://doi.org/10.1186/s11658-019-0152-2

  25. 25.

    Feng Y, Li Q, Wu Y, Zhao N, Li L, Li L, Zhao L (2019) Blocking C/EBP beta protects vascular endothelial cells from injury induced by intermittent hypoxia. Sleep Breath 23:953–962. https://doi.org/10.1007/s11325-018-1759-7

  26. 26.

    Du Y, Ge Y, Xu Z, Aa N, Gu X, Meng H, Lin Z, Zhu D, Shi J, Zhuang R, Wu X, Wang X, Yang Z (2018) Hypoxia-inducible factor 1 alpha (HIF-1alpha)/vascular endothelial growth factor (VEGF) pathway participates in angiogenesis of myocardial infarction in muscone-treated mice: preliminary study. Med Sci Monit 24:8870–8877. https://doi.org/10.12659/msm.912051

  27. 27.

    Cheng F, Lan J, Xia W, Tu C, Chen B, Li S, Pan W (2016) Folic acid attenuates vascular endothelial cell injury caused by hypoxia via the inhibition of ERK1/2/NOX4/ROS pathway. Cell Biochem Biophys 74:205–211. https://doi.org/10.1007/s12013-016-0723-z

  28. 28.

    Liu B, Che W, Xue J, Zheng C, Tang K, Zhang J, Wen J, Xu Y (2013) SIRT4 prevents hypoxia-induced apoptosis in H9c2 cardiomyoblast cells. Cell Physiol Biochem 32:655–662. https://doi.org/10.1159/000354469

  29. 29.

    Zhang X, Liu S, Weng X, Zeng S, Yu L, Guo J, Xu Y (2018) Brg1 deficiency in vascular endothelial cells blocks neutrophil recruitment and ameliorates cardiac ischemia-reperfusion injury in mice. Int J Cardiol 269:250–258. https://doi.org/10.1016/j.ijcard.2018.07.105

  30. 30.

    Xiao X, Xu S, Li L, Mao M, Wang J, Li Y, Wang Z, Ye F, Huang L (2017) The effect of velvet antler proteins on cardiac microvascular endothelial cells challenged with ischemia-hypoxia. Front Pharmacol 8:601. https://doi.org/10.3389/fphar.2017.00601

  31. 31.

    Tsai HH, Lin CP, Lin YH, Hsu CC, Wang JS (2016) High-intensity Interval training enhances mobilization/functionality of endothelial progenitor cells and depressed shedding of vascular endothelial cells undergoing hypoxia. Eur J Appl Physiol 116:2375–2388. https://doi.org/10.1007/s00421-016-3490-z

  32. 32.

    Zhang Q, Shang M, Zhang M, Wang Y, Chen Y, Wu Y, Liu M, Song J, Liu Y (2016) Microvesicles derived from hypoxia/reoxygenation-treated human umbilical vein endothelial cells promote apoptosis and oxidative stress in H9c2 cardiomyocytes. BMC Cell Biol 17:25. https://doi.org/10.1186/s12860-016-0100-1

  33. 33.

    Lee SH, Fujioka S, Takahashi R, Oe T (2019) Angiotensin II-induced oxidative stress in human endothelial cells: modification of cellular molecules through lipid peroxidation. Chem Res Toxicol 32:1412–1422. https://doi.org/10.1021/acs.chemrestox.9b00110

  34. 34.

    Chang PK, Yen IC, Tsai WC, Chang TC, Lee SY (2018) Protective effects of Rhodiola crenulata extract on hypoxia-induced endothelial damage via regulation of AMPK and ERK pathways. Int J Mol Sci 19:2286. https://doi.org/10.3390/ijms19082286

  35. 35.

    Wang Q, Lu G, Chen Z (2019) MALAT1 promoted cell proliferation and migration via MALAT1/miR-155/MEF2A pathway in hypoxia of cardiac stem cells. J Cell Biochem 120:6384–6394. https://doi.org/10.1002/jcb.27925

  36. 36.

    Wang LQ, Zhou HJ (2018) LncRNA MALAT1 promotes high glucose-induced inflammatory response of microglial cells via provoking MyD88/IRAK1/TRAF6 signaling. Sci Rep 8:8346. https://doi.org/10.1038/s41598-018-26421-5

  37. 37.

    Fang L, Ellims AH, Moore XL, White DA, Taylor AJ, Chin-Dusting J, Dart AM (2015) Circulating microRNAs as biomarkers for diffuse myocardial fibrosis in patients with hypertrophic cardiomyopathy. J Transl Med 13:314. https://doi.org/10.1186/s12967-015-0672-0

  38. 38.

    Wang KJ, Zhao X, Liu YZ, Zeng QT, Mao XB, Li SN, Zhang M, Jiang C, Zhou Y, Qian C, Feng KG, Guan HQ, Tang TT, Cheng X, Chen ZJ (2016) Circulating MiR-19b-3p, MiR-134-5p and MiR-186-5p are promising novel biomarkers for early diagnosis of acute myocardial infarction. Cell Physiol Biochem 38:1015–1029. https://doi.org/10.1159/000443053

  39. 39.

    Xue Y, Wei Z, Ding H, Wang Q, Zhou Z, Zheng S, Zhang Y, Hou D, Liu Y, Zen K, Zhang CY, Li J, Wang D, Jiang X (2015) MicroRNA-19b/221/222 induces endothelial cell dysfunction via suppression of PGC-1alpha in the progression of atherosclerosis. Atherosclerosis 241:671–681. https://doi.org/10.1016/j.atherosclerosis.2015.06.031

  40. 40.

    Lambert CM, Roy M, Robitaille GA, Richard DE, Bonnet S (2010) HIF-1 inhibition decreases systemic vascular remodelling diseases by promoting apoptosis through a hexokinase 2-dependent mechanism. Cardiovasc Res 88:196–204. https://doi.org/10.1093/cvr/cvq152

  41. 41.

    Heikal L, Ghezzi P, Mengozzi M, Ferns G (2018) Assessment of HIF-1alpha expression and release following endothelial injury in-vitro and in-vivo. Mol Med 24:22. https://doi.org/10.1186/s10020-018-0026-5

  42. 42.

    Semenza GL (2014) Hypoxia-inducible factor 1 and cardiovascular disease. Annu Rev Physiol 76:39–56. https://doi.org/10.1146/annurev-physiol-021113-170322

  43. 43.

    Loboda A, Jozkowicz A, Dulak J (2012) HIF-1 versus HIF-2—is one more important than the other? Vascul Pharmacol 56:245–251. https://doi.org/10.1016/j.vph.2012.02.006

  44. 44.

    Gao L, Chen Q, Zhou X, Fan L (2012) The role of hypoxia-inducible factor 1 in atherosclerosis. J Clin Pathol 65:872–876. https://doi.org/10.1136/jclinpath-2012-200828

  45. 45.

    Wu X, He L, Chen F, He X, Cai Y, Zhang G, Yi Q, He M, Luo J (2014) Impaired autophagy contributes to adverse cardiac remodeling in acute myocardial infarction. PLoS ONE 9:e112891–e112891. https://doi.org/10.1371/journal.pone.0112891

  46. 46.

    Zhu H, Tannous P, Johnstone JL, Kong Y, Shelton JM, Richardson JA, Le V, Levine B, Rothermel BA, Hill JA (2007) Cardiac autophagy is a maladaptive response to hemodynamic stress. J Clin Invest 117:1782–1793. https://doi.org/10.1172/jci27523

  47. 47.

    Luo Y, Lu S, Zhou P, Ai QD, Sun GB, Sun XB (2016) Autophagy: an exposing therapeutic target in atherosclerosis. J Cardiovasc Pharmacol 67:266–274. https://doi.org/10.1097/fjc.0000000000000342

  48. 48.

    Mellor KM, Bell JR, Young MJ, Ritchie RH, Delbridge LM (2011) Myocardial autophagy activation and suppressed survival signaling is associated with insulin resistance in fructose-fed mice. J Mol Cell Cardiol 50:1035–1043. https://doi.org/10.1016/j.yjmcc.2011.03.002

  49. 49.

    Duan J, Yu Y, Li Y, Jing L, Yang M, Wang J, Li Y, Zhou X, Miller MR, Sun Z (2017) Comprehensive understanding of PM2.5 on gene and microRNA expression patterns in zebrafish (Danio rerio) model. Sci Total Environ 586:666–674. https://doi.org/10.1016/j.scitotenv.2017.02.042

  50. 50.

    Huang S, Qi P, Zhang T, Li F, He X (2019) The HIF-1α/miR-224-3p/ATG5 axis affects cell mobility and chemosensitivity by regulating hypoxia-induced protective autophagy in glioblastoma and astrocytoma. Oncol Rep 41:1759–1768. https://doi.org/10.3892/or.2018.6929

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Correspondence to Yongzhi Deng.

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Liu, H., Shi, C. & Deng, Y. MALAT1 affects hypoxia-induced vascular endothelial cell injury and autophagy by regulating miR-19b-3p/HIF-1α axis. Mol Cell Biochem (2020). https://doi.org/10.1007/s11010-020-03684-z

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Keywords

  • Metastasis associated lung adenocarcinoma transcript 1
  • miR-19b-3p
  • Hypoxia inducible factor-1α
  • Apoptosis
  • Autophagy
  • Inflammation