MicroRNAs in Cerebrovascular Diseases –  from Pathophysiology to Potential Biomarkers

Authors: O. Volný 1,2;  L. Kašičková 3;  D. Coufalová 2,3;  P. Cimflová 2,4;  J. Novák 5,6
Authors‘ workplace: I. neurologická klinika LF MU a FN u sv. Anny v Brně 1;  ICRC – Mezinárodní centrum klinického výzkumu, FN u sv. Anny v Brně 2;  Lékařská fakulta MU, Brno 3;  Klinika zobrazovacích metod LF MU a FN u sv. Anny v Brně 4;  II. interní klinika LF MU a FN U sv. Anny v Brně 5;  Fyziologický ústav, LF MU, Brno 6
Published in: Cesk Slov Neurol N 2016; 79/112(3): 287-293
Category: Review Article


Small non-coding molecules of ribonucleic acid are important regulators of gene expression and translation. One group of non-coding RNAs is represented by microRNA – 22-24 nucleotides long RNA molecules with effects on regulation of proteins synthesis. Many of them are tissue or organ specific (e. g. miR-206 in striated muscles or miR-122 in hepatocytes). These molecules are enzyme-resistant and detectable in both intracellular and extracellular space. Currently, these molecules are intensively studied as potential markers in many diseases including cerebrovascular diseases. In this review we provide insight into the recent knowledge from animal to human studies concerning miRNAs, with the special emphasis put on diagnostic, therapeutic and prognostic potentials in ischemic stroke (let-7, miR-7, miR-21, miR-29, miR-124, miR-181, miR-210, miR-223), intracranial aneurysms (miR-21, miR-26, miR-29, miR-143/145), and brain arterio-venous malformations (miR-18a).

Key words:
microRNA – ischemic stroke – intracranial aneurysma – cerebral arterio-venous malformations

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.


1. Estel­ler M. Non-cod­ing RNAs in human disease. Nat Rev Genet 2011;12(12):861– 74. doi: 10.1038/nrg3074.

2. Bartel DP. MicroRNAs: genomics, bio­genesis, mechanism, and function. Cell 2004;116(2):281– 97.

3. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993;75(5):843– 54.

4. Reinhart BJ, Slack FJ, Bas­son M, et al. The 21-nucleotide let-7 RNA regulates developmental tim­ing in Caenorhab­ditis elegans. Nature 2000;403(6772):901– 6.

5. Pasquinel­li AE, Reinhart BJ, Slack F, et al. Conservation of the sequence and temporal expres­sion of let-7 heterochronic regulatory RNA. Nature 2000;408(6808):86– 9.

6. Calin GA, Dumitru CD, Shimizu M, et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 2002;99(24):15524– 9.

7. Weber JA, Baxter DH, Zhang S, et al. The microRNA spectrum in 12 body fluids. Clin Chem 2010;56(11):1733– 41. doi: 10.1373/clinchem.2010.147405.

8. Kondkar AA, Abu-Amero KK. Utility of circulat­ing microRNAs as clinical bio­markers for cardiovascular diseases. BioMed Res Int 2015;2015:821823. doi: 10.1155/2015/ 821823.

9. Zhang W, Qian P, Zhang X, et al. Autocrine/ Paracrine Human Growth Hormone-stimulated MicroRNA 96-182-183 Cluster Promotes Epithelial-Mesenchymal Transition and Invasion in Breast Cancer. J Biol Chem 2015;290(22):13812– 29. doi: 10.1074/jbc.M115.653261.

10. Madon­na R, Cadeddu C, Deidda M, et al. Cardioprotection by gene therapy: a review paper on behalf of the Work­ing Group on Drug Cardiotoxicity and Cardioprotection of the Italian Society of Cardiology. Int J Cardiol 2015;191:203– 10. doi: 10.1016/j.ijcard.2015.04.232.

11. Chen X, Zhang L, Su T, et al. Kinetics of plasma microRNA-499 expres­sion in acute myocardial infarction. J Thorac Dis 2015;7(5):890– 6. doi: 10.3978/j.is­sn.2072-1439.2014.11.32.

12. Ar­rese M, Eguchi A, Feldstein AE. Circulat­ing microRNAs: emerg­ing bio­markers of liver disease. Semin Liver Dis 2015;35(1):43– 54. doi: 10.1055/s-0034-1397348.

13. van Rooij E, Olson EN. MicroRNA therapeutics for cardiovascular disease: opportunities and obstacles. Nat Rev Drug Discov 2012;11(11):860– 72. doi: 10.1038/nrd3864.

14. Rayner KJ, Esau CC, Hus­sain FN, et al. Inhibition of miR-33a/ b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Nature 2011;478(7369):404– 7. doi: 10.1038/nature10486.

15. Rayner KJ, Sheedy FJ, Esau CC, et al. Antagonism of miR-33 in mice promotes reverse cholesterol transport and regres­sion of atherosclerosis. J Clin Invest 2011;121(7):2921– 31. doi: 10.1172/JCI57275.

16. Wahlquist C, Jeong D, Rojas-Muñoz A, et al. Inhibition of miR-25 improves cardiac contractility in the fail­ing heart. Nature 2014;508(7497):531– 5. doi: 10.1038/nature13073.

17. Jans­sen HL, Reesink HW, Lawitz EJ, et al. Treatment of HCV infection by target­ing microRNA. N Engl J Med 2013;368(18):1685– 94. doi: 10.1056/NEJMoa1209026.

18. Soreq H, Wolf Y. Neurim­miRs: microRNAs in the neuroim­mune interface. Trends Mol Med 2011;17(10):548– 55. doi: 10.1016/j.molmed.2011.06.009.

19. Kim JM, Jung KH, Chu K, et al. Atherosclerosis-related circulat­ing microRNAs as a predictor of strokerecur­rence. Transl Stroke Res 2015;6(3):191– 7. doi: 10.1007/s12975-015-0390-1.

20. Dharap A, Bowen K, Place R, et al. Transient focal ischemia induces extensive temporal changes in rat cerebral microRNAome. J Cereb Blood Flow Metab 2009;29(4):675– 87. doi: 10.1038/jcbfm.2008.157.

21. Gubern C, Camós S, Bal­lesteros I, et al. miRNA expres­sion is modulated over time after focal ischaemia: up-regulation of miR-347 promotes neuronal apoptosis. FEBS J 2013;280(23):6233– 46. doi: 10.1111/febs.12546.

22. Jeyaseelan K, Lim KY, Armugam A. MicroRNA expres­sion in the blood and brain of rats subjected to transient focal ischemia by middle cerebral artery occlusion. Stroke J Cereb Circ 2008;39(3):959– 66.

23. Liu FJ, Lim KY, Kaur P, et al. microRNAs involved in regulat­ing spontaneous recovery in embolic stroke model. PloS One 2013;8(6):e66393.

24. Selvamani A, Wil­liams MH, Miranda RC, et al. Circulat­ing miRNA profiles provide a bio­marker for severity of stroke outcomes as­sociated with age and sex in a rat model. Clin Sci Lond Engl 2014;127(2):77– 89. doi: 10.1042/CS20130565.

25. Weng H, Shen C, Hirokawa G, et al. Plasma miR--124 as a bio­marker for cerebral infarction. Biomed Res 2011;32(2):135– 41.

26. Rehfeld F, Rohde AM, Nguyen DT, et al. Lin28 and let-7: ancient milestones on the road from pluripotency to neurogenesis. Cell Tis­sue Res 2015;359(1):145– 60. doi: 10.1007/s00441-014-1872-2.

27. Hulsmans M, Holvoet P. MicroRNA-contain­ing microvesicles regulat­ing inflam­mation in as­sociation with atherosclerotic disease. Cardiovasc Res 2013;100(1):7– 18. doi: 10.1093/cvr/cvt161.

28. Valadi H, Ekström K, Bos­sios A, et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cel­ls. Nat Cell Biol 2007;9(6):654– 9.

29. Selvamani A, Sathyan P, Miranda RC, et al. An antagomir to microRNA Let7f promotes neuroprotection in an ischemic stroke model. PloS One 2012;7(2):e32662. doi: 10.1371/journal.pone.0032662.

30. Bienertova-Vasku J, Novak J, Vasku A. MicroRNAs in pulmonary arterial hypertension: pathogenesis, dia­gnosis and treatment. J Am Soc Hypertens 2015;9(3):221– 34. doi: 10.1016/j.jash.2014.12.011.

31. Tan KS, Armugam A, Se pramaniam S, et al. Expres­sion profile of MicroRNAs in young stroke patients. PloS One 2009;4(11):e7689. doi: 10.1371/ journal.pone.0007689.

32. Bul­ler B, Liu X, Wang X, et al. MicroRNA-21 protects neurons from ischemic death. FEBS J 2010;277(20):4299– 307. doi: 10.1111/j.1742-4658.2010.07818.x.

33. Zhou J, Zhang J. Identification of miRNA-21 and miRNA-24 in plasma as potential early stage markers of acute cerebral infarction. Mol Med Rep 2014;10(2):971– 6. doi: 10.3892/m­mr.2014.2245.

34. 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(43):29514– 25. doi: 10.1074/jbc.M109.027896.

35. Huang LG, Li JP, Pang XM, et al. MicroRNA-29c Cor­relates with Neuroprotection Induced by FNS by Target­ing Both Birc2 and Bak1 in Rat Brain after Stroke. CNS Neurosci Ther 2015;21(6):496– 503. doi: 10.1111/cns.12383.

36. Khan­na S, Rink C, Ghoorkhanian R, et al. Loss of miR-29b fol­low­ing acute ischemic stroke contributes to neural cell death and infarct size. J Cereb Blood Flow Metab 2013;33(8):1197– 206. doi: 10.1038/jcbfm.2013.68.

37. Pandi G, Nakka VP, Dharap A, et al. MicroRNA miR-29c down-regulation lead­ing to de-repres­sion of its target DNA methyltransferase 3a promotes ischemic brain damage. PloS One 2013;8(3):e58039. doi: 10.1371/journal.pone.0058039.

38. Dhiraj DK, Chrysanthou E, Mal­lucci GR, et al. miRNAs-19b, -29b-2* and -339-5p show an early and sustained up-regulation in ischemic models of stroke. PloS One 2013;8(12):e83717. doi: 10.1371/journal.pone.0083717.

39. Shi G, Liu Y, Liu T, et al. Upregulated miR-29b promotes neuronal cell death by inhibit­ing Bcl2L2 after ischemic brain injury. Exp Brain Res 2012;216(2):225– 30. doi: 10.1007/s00221-011-2925-3.

40. Laterza OF, Lim L, Gar­rett-Engele PW, et al. Plasma MicroRNAs as sensitive and specific bio­markers of tis­sue injury. Clin Chem 2009;55(11):1977– 83. doi: 10.1373/clinchem.2009.131797.

41. Meza-Sosa KF, Pedraza-Alva G, Pérez-Martínez L. MicroRNAs: key triggers of neuronal cell fate. Front Cell Neurosci 2014;8:175. doi: 10.3389/fncel.2014.00175.

42. Doeppner TR, Doehr­ing M, Bretschneider E, et al. MicroRNA-124 protects against focal cerebral ischemia via mechanisms involv­ing Usp14-dependent REST degradation. Acta Neuropathol 2013;126(2):251– 65. doi: 10.1007/s00401-013-1142-5.

43. Sun Y, Gui H, Li Q, et al. MicroRNA-124 protects neurons against apoptosis in cerebral ischemic stroke. CNS Neurosci Ther 2013;19(10):813– 9. doi: 10.1111/cns.12142.

44. Fang M, Wang J, Zhang X, et al. The miR-124 regulates the expres­sion of BACE1/ β-secretase cor­related with cell death in Alzheimer’s disease. Toxicol Lett 2012;209(1):94– 105. doi: 10.1016/j.toxlet.2011.11.032.

45. Liu XS, Chopp M, Zhang RL, et al. MicroRNA profil­ing in subventricular zone after stroke: MiR-124a regulates proliferation of neural progenitor cel­ls through Notch signal­ing pathway. PloS One 2011;6(8):e23461. doi: 10.1371/journal.pone.0023461.

46. Zhu F, Liu JL, Li JP, et al. MicroRNA-124 (miR-124) regulates Ku70 expres­sion and is cor­related with neuronal death induced by ischemia/ reperfusion. J Mol Neurosci 2014;52(1):148– 55. doi: 10.1007/s12031-013-0155-9.

47. Miska EA, Alvarez-Saavedra E, Townsend M, et al.Microar­ray analysis of microRNA expres­sion in the develop­ing mam­malian brain. Genome Biol 2004;5(9):R68.

48. Ouyang YB, Gif­fard RG. MicroRNAs af­fect BCL-2 family proteins in the sett­ing of cerebral ischemia. Neurochem Int 2014;77:2– 8. doi: 10.1016/j.neuint.2013.12.006.

49. Ouyang YB, Lu Y, Yue S, et al. miR-181 regulates GRP78 and influences outcome from cerebral ischemia in vitro and in vivo. Neurobio­l Dis 2012;45(1):555– 63. doi: 10.1016/j.nbd.2011.09.012.

50. Ouyang YB, Gif­fard RG. MicroRNAs regulate the chaperone network in cerebral ischemia. Transl Stroke Res 2013;4(6):693– 703. doi: 10.1007/s12975-013-0280-3.

51. Ouyang YB, Xu L, Liu S, et al. Role of astrocytes in delayed neuronal death: GLT-1 and its novel regulation by MicroRNAs. Adv Neurobio­l 2014;11:171– 88. doi: 10.1007/978-3-319-08894-5_9.

52. Chan YC, Banerjee J, Choi SY, et al. miR-210: the master hypoxamir. Microcirc 2012;19(3):215– 23. doi: 10.1111/j.1549-8719.2011.00154.x.

53. Fasanaro P, D’Ales­sandra Y, Di Stefano V, et al. MicroRNA-210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine kinase ligand Ephrin-A3. J Biol Chem 2008;283(23):15878– 83. doi: 10.1074/jbc.M800731200.

54. Lou L, Guo F, Liu F, et al. miR-210 activates notch signal­ing pathway in angiogenesis induced by cerebral ischemia. Mol Cell Biochem 2012;370(1– 2):45– 51. doi: 10.1007/s11010-012-1396-6.

55. Zeng L, He X, Wang Y, et al. MicroRNA-210 overexpres­sion induces angiogenesis and neurogenesis in the normal adult mouse brain. Gene Ther 2014;21(1):37– 43. doi: 10.1038/gt.2013.55.

56. Sepramaniam S, Y­ing LK, Armugam A, et al. MicroRNA-130a repres­ses transcriptional activity of aquaporin 4 M1 promoter. J Biol Chem 2012;287(15):12006– 15. doi: 10.1074/jbc.M111.280701.

57. Pan Y, Liang H, Liu H, et al. Platelet-secreted microRNA-223 promotes endothelial cell apoptosis induced by advanced glycation end products via target­ing the insulin-like growth factor 1 receptor. J Im­munol Baltim Md 2014;192(1):437– 46. doi: 10.4049/jim­munol.1301790.

58. Tabet F, Vickers KC, Cuesta Tor­res LF, et al. HDL--transfer­red microRNA-223 regulates ICAM-1 expres­sion in endothelial cel­ls. Nat Com­mun 2014;5:3292. doi: 10.1038/ncom­ms4292.

59. Vickers KC, Landstreet SR, Levin MG, et al. MicroRNA-223 coordinates cholesterol homeostasis. Proc Natl Acad Sci U S A 2014;111(40):14518– 23. doi: 10.1073/pnas.1215767111.

60. Har­raz MM, Eacker SM, Wang X, et al. MicroRNA-223 is neuroprotective by target­ing glutamate receptors. Proc Natl Acad Sci U S A 2012;109(46):18962– 7. doi: 10.1073/ pnas.1121288109.

61. Duan X, Zhan Q, Song B, et al. Detection of platelet microRNA expres­sion in patients with diabetes mel­litus with or without ischemic stroke. J Diabetes Complications 2014;28(5):705– 10. doi: 10.1016/j.jdiacomp.2014.04.012.

62. Leung LY, Chan CP, Leung YK, et al. Comparison of miR-124-3p and miR-16 for early dia­gnosis of hemor­rhagic and ischemic stroke. Clin Chim Acta 2014;433:139– 44. doi: 10.1016/j.cca.2014.03.007.

63. Liu Y, Zhang J, Han R, et al. Downregulation of serum brain specific microRNA is as­sociated with inflam­mation and infarct volume in acute ischemic stroke. J Clin Neurosci 2015;22(2):291– 5. doi: 10.1016/j.jocn.2014.05.042.

64. Long G, Wang F, Li H, et al. Circulat­ing miR-30a, miR--126 and let-7b as bio­marker for ischemic stroke in humans. BMC Neurol 2013;13:178. doi: 10.1186/1471-2377-13-178.

65. Tsai PC, Liao YC, Wang Y-S, et al. Serum microRNA-21 and microRNA-221 as potential bio­markers for cerebrovascular disease. J Vasc Res 2013;50(4):346– 54. doi: 10.1159/000351767.

66. Zeng L, Liu J, Wang Y, et al. MicroRNA-210 as a novel blood bio­marker in acute cerebral ischemia. Front Biosci 2011;3:1265– 72.

67. Wang Y, Zhang Y, Huang J, et al. Increase of circulat­ing miR-223 and insulin-like growth factor-1 is as­sociated with the pathogenesis of acute ischemic stroke in patients. BMC Neurol 2014;14:77. doi: 10.1186/1471-2377-14-77.

68. Vinciguer­ra A, Formisano L, Cerul­lo P, et al. MicroRNA--103-1 selectively downregulates brain NCX1 and its inhibition by anti-miRNA ameliorates stroke damage and neurological deficits. Mol Ther 2014;22(10):1829– 38. doi: 10.1038/mt.2014.113.

69. Yang ZB, Zhang Z, Li TB, et al. Up-regulation of brain-enriched miR-107 promotes excitatory neurotoxicity through down-regulation of glutamate transporter-1 expres­sion fol­low­ing ischaemic stroke. Clin Sci Lond Engl 2014;127(12):679– 89. doi: 10.1042/CS20140084.

70. Chi W, Meng F, Li Y, et al. Downregulation of miRNA--134 protects neural cel­ls against ischemic injury in N2A cel­ls and mouse brain with ischemic stroke by target­ing HSPA12B. Neuroscience 2014;277:111– 22. doi: 10.1016/j.neuroscience.2014.06.062.

71. Chi W, Meng F, Li Y, et al. Impact of microRNA-134 on neural cell survival against ischemic injury in primary cultured neuronal cel­ls and mouse brain with ischemic stroke by target­ing HSPA12B. Brain Res 2014;1592:22– 33. doi: 10.1016/j.brainres.2014.09.072.

72. Stary CM, Xu L, Sun X, et al. MicroRNA-200c contributes to injury from transient focal cerebral ischemia by target­ing Reelin. Stroke 2015;46(2):551– 6. doi: 10.1161/STROKEAHA.114.007041.

73. Li LJ, Huang Q, Zhang N, et al. miR-376b-5p regulates angiogenesis in cerebral ischemia. Mol Med Rep 2014;10(1):527– 35. doi: 10.3892/m­mr.2014.2172.

74. Liu P, Zhao H, Wang R, et al. MicroRNA-424 protects against focal cerebral ischemia and reperfusion injury in mice by suppres­s­ing oxidative stres­s. Stroke 2015;46(2):513– 9. doi: 10.1161/STROKEAHA.114.007482.

75. Zhao H, Wang J, Gao L, et al. MiRNA-424 protects against permanent focal cerebral ischemia injury in mice involv­ing suppres­s­ing microglia activation. Stroke 2013;44(6):1706– 13. doi: 10.1161/STROKEAHA.111.000504.

76. Brown RD, Wiebers DO, Forbes GS. Unruptured intracranial aneurysms and arteriovenous malformations: frequency of intracranial hemor­rhage and relationship of lesions. J Neurosur 1990;73(6):859– 63.

77. Brown RD, Broderick JP. Unruptured intracranial aneurysms: epidemiology, natural history, management options, and familial screening. Lancet Neurol 2014;13(4):393– 404. doi: 10.1016/S1474-4422(14)70015-8.

78. Shiue I, Arima H, Hankey GJ, et al. Modifiable lifestyle behaviours account for most cases of subarachnoid haemor­rhage: a population-based case-control study in Australasia. J Neurol Sci 2012;313(1– 2):92– 4. doi: 10.1016/j.jns.2011.09.017.

79. Vernooij MW, Ikram MA, Tanghe HL, et al. Incidental findings on brain MRI in the general population. N Engl J Med 2007;357(18):1821– 8.

80. Lee HJ, Yi JS, Lee HJ, et al. Dysregulated expres­sion profiles of microRNAs of experimental­ly induced cerebral aneurysms in rats. J Korean Neurosurg Soc 2013;53(2):72– 6. doi: 10.3340/jkns.2013.53.2.72.

81. Jiang Y, Zhang M, He H, et al. MicroRNA/ mRNA profil­ing and regulatory network of intracranial aneurysm. BMC Med Genomics 2013;6:36. doi: 10.1186/1755-8794-6-36.

82. Liu D, Han L, Wu X, et al. Genome-wide microRNA changes in human intracranial aneurysms. BMC Neurol 2014;14(1):188. doi: 10.1186/s12883-014-0188-x.

83. Jin H, Li C, Ge H, et al. Circulat­ing microRNA: a novel potential bio­marker for early dia­gnosis of intracranial aneurysm rupture a case control study. J Transl Med 2013;11:296. doi: 10.1186/1479-5876-11-296.

84. Li P, Zhang Q, Wu X, et al. Circulat­ing microRNAs serve as novel bio­logical markers for intracranial aneurysms. J Am Heart As­soc 2014;3(5):e000972. doi: 10.1161/JAHA.114.000972.

85. Maegdefes­sel L, Azuma J, Toh R, et al. MicroRNA-21 blocks abdominal aortic aneurysm development and nicotine-augmented expansion. Sci Transl Med 2012;4(122):22. doi: 10.1126/scitranslmed.3003441.

86. Boon RA, Seeger T, Heydt S, et al. MicroRNA-29 in aortic dilation: implications for aneurysm formation. Circ Res 2011;109(10):1115– 9. doi: 10.1161/CIRCRESAHA.111.255737.

87. Maegdefes­sel L, Azuma J, Tsao PS. MicroRNA-29b regulation of abdominal aortic aneurysm development. Trends Cardiovasc Med 2014;24(1):1– 6. doi: 10.1016/j.tcm.2013.05.002.

88. Merk DR, Chin JT, Dake BA, et al. MiR-29b participates in early aneurysm development in Marfan syndrome. Circ Res 2012;110(2):312– 24. doi: 10.1161/CIRCRESAHA.111.253740.

89. Elia L, Quintaval­le M, Zhang J, et al. The knockout of miR-143 and -145 alters smooth muscle cell maintenance and vascular homeostasis in mice: cor­relates with human disease. Cell Death Dif­fer 2009;16(12):1590– 8. doi: 10.1038/cdd.2009.153.

90. Doebele C, Bonauer A, Fischer A, et al. Members of the microRNA-17-92 cluster exhibit a cel­l-intrinsic antiangiogenic function in endothelial cel­ls. Blood 2010;115(23):4944– 50. doi: 10.1182/blood-2010-01-264812.

91. Fer­reira R, Santos T, Amar A, et al. Argonaute-2 promotes miR-18a entry in human brain endothelial cel­ls. J Am Heart As­soc 2014;3(3):e000968. doi: 10.1161/JAHA.114.000968.

92. Fer­reira R, Santos T, Amar A, et al. MicroRNA-18a improves human cerebral arteriovenous malformation endothelial cell function. Stroke 2014;45(1):293– 7. doi: 10.1161/STROKEAHA.113.003578.

Paediatric neurology Neurosurgery Neurology

Article was published in

Czech and Slovak Neurology and Neurosurgery

Issue 3

2016 Issue 3

Most read in this issue
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account