Top

Published in:

Open Access 01-11-2018 | Brief Communication

eNOS expression and NO release during hypoxia is inhibited by miR-200b in human endothelial cells

Authors: Anna Janaszak-Jasiecka, Anna Siekierzycka, Sylwia Bartoszewska, Marcin Serocki, Lawrence W. Dobrucki, James F. Collawn, Leszek Kalinowski, Rafal Bartoszewski

Published in: Angiogenesis | Issue 4/2018

Abstract

The nitric oxide (NO) secreted by vascular endothelium is required for the maintenance of cardiovascular homeostasis. Diminished release of NO generated by endothelial NO synthase contributes to endothelial dysfunction. Hypoxia and ischemia reduce endothelial eNOS expression via posttranscriptional mechanisms that result in NOS3 transcript destabilization. Here, we examine whether microRNAs contribute to this mechanism. We followed the kinetics of hypoxia-induced changes in NOS3 mRNA and eNOS protein levels in primary human umbilical vein endothelial cells (HUVECs). Utilizing in silico predictive protocols to identify potential miRNAs that regulate eNOS expression, we identified miR-200b as a candidate. We established the functional miR-200b target sequence within the NOS3 3′UTR, and demonstrated that manipulation of the miRNA levels during hypoxia using miR-200b mimics and antagomirs regulates eNOS levels, and established that miR-200b physiologically limits eNOS expression during hypoxia. Furthermore, we demonstrated that the specific ablation of the hypoxic induction of miR-200b in HUVECs restored eNOS-driven hypoxic NO release to the normoxic levels. To determine whether miR-200b might be the only miRNA that had this effect, we utilized Next Generation Sequencing (NGS) to follow hypoxia-induced changes in the miRNA levels in HUVECS and found 83 novel hypoxamiRs, with two candidate miRNAs besides miR-200b that could potentially influence eNOS levels. Taken together, the data establish miR-200b-eNOS regulation as a first hypoxamiR-based mechanism that limits NO bioavailability during hypoxia in endothelial cells, and show that hypoxamiRs could become useful therapeutic targets for cardiovascular diseases and other hypoxic-related diseases including various types of cancer.

Available only for authorised users

Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S (2009) Endothelial dysfunction as a target for prevention of cardiovascular disease. Diabetes Care 32(Suppl 2):S314–S321. https://doi.org/10.2337/dc09-S330 CrossRefPubMedPubMedCentral

Yang X, Chang Y, Wei W (2016) Endothelial dysfunction and inflammation: immunity in rheumatoid arthritis. Mediat Inflamm 2016:6813016. https://doi.org/10.1155/2016/6813016 CrossRef

Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, Sessa WC (1999) Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399(6736):597–601. https://doi.org/10.1038/21218 CrossRefPubMedPubMedCentral

Ziegler T, Silacci P, Harrison VJ, Hayoz D (1998) Nitric oxide synthase expression in endothelial cells exposed to mechanical forces. Hypertension 32 (2):351–355CrossRefPubMed

Searles CD (2006) Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression. Am J Physiol Cell Physiol 291(5):C803–C816. https://doi.org/10.1152/ajpcell.00457.2005 CrossRefPubMed

Kalinowski L, Janaszak-Jasiecka A, Siekierzycka A, Bartoszewska S, Wozniak M, Lejnowski D, Collawn JF, Bartoszewski R (2016) Posttranscriptional and transcriptional regulation of endothelial nitric-oxide synthase during hypoxia: the role of microRNAs. Cell Mol Biol Lett 21:16. https://doi.org/10.1186/s11658-016-0017-x CrossRefPubMedPubMedCentral

Drummond GR, Cai H, Davis ME, Ramasamy S, Harrison DG (2000) Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression by hydrogen peroxide. Circ Res 86(3):347–354. https://doi.org/10.1161/01.res.86.3.347 CrossRefPubMed

Olson N, van der Vliet A (2011) Interactions between nitric oxide and hypoxia-inducible factor signaling pathways in inflammatory disease. Nitric Oxide 25(2):125–137. https://doi.org/10.1016/j.niox.2010.12.010 CrossRefPubMedPubMedCentral

Coulet F, Nadaud S, Agrapart M, Soubrier F (2003) Identification of hypoxia-response element in the human endothelial nitric-oxide synthase gene promoter. J Biol Chem 278(47):46230–46240. https://doi.org/10.1074/jbc.M305420200 CrossRefPubMed

10.

McQuillan LP, Leung GK, Marsden PA, Kostyk SK, Kourembanas S (1994) Hypoxia inhibits expression of eNOS via transcriptional and posttranscriptional mechanisms. Am J Physiol 267(5 Pt 2):H1921–H1927PubMed

11.

Fish JE, Matouk CC, Yeboah E, Bevan SC, Khan M, Patil K, Ohh M, Marsden PA (2007) Hypoxia-inducible expression of a natural cis-antisense transcript inhibits endothelial nitric-oxide synthase. J Biol Chem 282(21):15652–15666. https://doi.org/10.1074/jbc.M608318200 CrossRefPubMed

12.

Ho JJ, Robb GB, Tai SC, Turgeon PJ, Mawji IA, Man HS, Marsden PA (2013) Active stabilization of human endothelial nitric oxide synthase mRNA by hnRNP E1 protects against antisense RNA and microRNAs. Mol Cell Biol 33(10):2029–2046. https://doi.org/10.1128/mcb.01257-12 CrossRefPubMedPubMedCentral

13.

Robb GB, Carson AR, Tai SC, Fish JE, Singh S, Yamada T, Scherer SW, Nakabayashi K, Marsden PA (2004) Post-transcriptional regulation of endothelial nitric-oxide synthase by an overlapping antisense mRNA transcript. J Biol Chem 279(36):37982–37996. https://doi.org/10.1074/jbc.M400271200 CrossRefPubMed

14.

Suárez Y, Fernández-Hernando C, Pober JS, Sessa WC (2007) Dicer dependent microRNAs regulate gene expression and functions in human endothelial cells. Circ Res 100(8):1164–1173. https://doi.org/10.1161/01.RES.0000265065.26744.17 CrossRefPubMed

15.

Sun HX, Zeng DY, Li RT, Pang RP, Yang H, Hu YL, Zhang Q, Jiang Y, Huang LY, Tang YB, Yan GJ, Zhou JG (2012) Essential role of microRNA-155 in regulating endothelium-dependent vasorelaxation by targeting endothelial nitric oxide synthase. Hypertension 60(6):1407–1414. https://doi.org/10.1161/HYPERTENSIONAHA.112.197301 CrossRefPubMed

16.

Chan LS, Yue PY, Mak NK, Wong RN (2009) Role of microRNA-214 in ginsenoside-Rg1-induced angiogenesis. Eur J Pharm Sci 38(4):370–377. https://doi.org/10.1016/j.ejps.2009.08.008 CrossRefPubMed

17.

Zhang W, Yan L, Li Y, Chen W, Hu N, Wang H, Ou H (2015) Roles of miRNA-24 in regulating endothelial nitric oxide synthase expression and vascular endothelial cell proliferation. Mol Cell Biochem 405(1–2):281–289. https://doi.org/10.1007/s11010-015-2418-y CrossRefPubMed

18.

Carlomosti F, D’Agostino M, Beji S, Torcinaro A, Rizzi R, Zaccagnini G, Maimone B, Di Stefano V, De Santa F, Cordisco S, Antonini A, Ciarapica R, Dellambra E, Martelli F, Avitabile D, Capogrossi MC, Magenta A (2017) Oxidative stress-induced miR-200c disrupts the regulatory loop among SIRT1, FOXO1, and eNOS. Antioxid Redox Signal 27(6):328–344. https://doi.org/10.1089/ars.2016.6643 CrossRefPubMed

19.

Madanecki P, Kapoor N, Bebok Z, Ochocka R, Collawn JF, Bartoszewski R (2013) Regulation of angiogenesis by hypoxia: the role of microRNA. Cell Mol Biol Lett 18(1):47–57. https://doi.org/10.2478/s11658-012-0037-0 CrossRefPubMed

20.

Bartoszewski R, Brewer JW, Rab A, Crossman DK, Bartoszewska S, Kapoor N, Fuller C, Collawn JF, Bebok Z (2011) The unfolded protein response (UPR)-activated transcription factor X-box-binding protein 1 (XBP1) induces microRNA-346 expression that targets the human antigen peptide transporter 1 (TAP1) mRNA and governs immune regulatory genes. J Biol Chem 286(48):41862–41870. https://doi.org/10.1074/jbc.M111.304956 CrossRefPubMedPubMedCentral

21.

Bartoszewski R, Rab A, Fu L, Bartoszewska S, Collawn J, Bebok Z (2011) CFTR expression regulation by the unfolded protein response. Methods Enzymol 491:3–24. https://doi.org/10.1016/B978-0-12-385928-0.00001-8 CrossRefPubMedPubMedCentral

22.

Bartoszewski R, Serocki M, Janaszak-Jasiecka A, Bartoszewska S, Kochan-Jamrozy K, Piotrowski A, Kroliczewski J, Collawn JF (2017) miR-200b downregulates Kruppel Like Factor 2 (KLF2) during acute hypoxia in human endothelial cells. Eur J Cell Biol 96(8):758–766. https://doi.org/10.1016/j.ejcb.2017.10.001 CrossRefPubMedPubMedCentral

23.

Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25(4):402–408. https://doi.org/10.1006/meth.2001.1262 CrossRefPubMed

24.

Kalinowski L, Dobrucki IT, Malinski T (2004) Race-specific differences in endothelial function: predisposition of African Americans to vascular diseases. Circulation 109(21):2511–2517. https://doi.org/10.1161/01.CIR.0000129087.81352.7A CrossRefPubMed

25.

Dobrucki LW, Marsh BJ, Kalinowski L (2009) Elucidating structure-function relationships from molecule-to-cell-to-tissue: from research modalities to clinical realities. J Physiol Pharmacol 60(Suppl 4):83–93PubMed

26.

Domagala TB, Szeffler A, Dobrucki LW, Dropinski J, Polanski S, Leszczynska-Wiloch M, Kotula-Horowitz K, Wojciechowski J, Wojnowski L, Szczeklik A, Kalinowski L (2012) Nitric oxide production and endothelium-dependent vasorelaxation ameliorated by N1-methylnicotinamide in human blood vessels. Hypertension 59(4):825–832. https://doi.org/10.1161/HYPERTENSIONAHA.111.183210 CrossRefPubMed

27.

Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3(7):RESEARCH0034CrossRefPubMedPubMedCentral

28.

McQuillan LP, Leung GK, Marsden PA, Kostyk SK, Kourembanas S (1994) Hypoxia inhibits expression of eNOS via transcriptional and posttranscriptional mechanisms. Am J Physiol 267(5):H1921–H1927PubMed

29.

Betel D, Koppal A, Agius P, Sander C, Leslie C (2010) Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites. Genome Biol 11(8):R90. https://doi.org/10.1186/gb-2010-11-8-r90 CrossRefPubMedPubMedCentral

30.

Agarwal V, Bell GW, Nam JW, Bartel DP (2015) Predicting effective microRNA target sites in mammalian mRNAs. Elife. https://doi.org/10.7554/eLife.05005 CrossRefPubMedPubMedCentral

31.

Janaszak-Jasiecka A, Bartoszewska S, Kochan K, Piotrowski A, Kalinowski L, Kamysz W, Ochocka RJ, Bartoszewski R, Collawn JF (2016) miR-429 regulates the transition between Hypoxia-Inducible Factor (HIF)1A and HIF3A expression in human endothelial cells. Sci Rep 6:22775. https://doi.org/10.1038/srep22775 CrossRefPubMedPubMedCentral

32.

Bartoszewska S, Kochan K, Piotrowski A, Kamysz W, Ochocka RJ, Collawn JF, Bartoszewski R (2015) The hypoxia-inducible miR-429 regulates hypoxia-inducible factor-1alpha expression in human endothelial cells through a negative feedback loop. FASEB J 29(4):1467–1479. https://doi.org/10.1096/fj.14-267054 CrossRefPubMed

33.

Ostergaard L, Stankevicius E, Andersen MR, Eskildsen-Helmond Y, Ledet T, Mulvany MJ, Simonsen U (2007) Diminished NO release in chronic hypoxic human endothelial cells. Am J Physiol Heart Circ Physiol 293(5):H2894-2903. https://doi.org/10.1152/ajpheart.01230.2006 CrossRef

34.

Kalinowski L, Malinski T (2004) Endothelial NADH/NADPH-dependent enzymatic sources of superoxide production: relationship to endothelial dysfunction. Acta Biochim Pol 51(2):459–469. doi:035001459PubMed

35.

Landmesser U, Hornig B, Drexler H (2004) Endothelial function: a critical determinant in atherosclerosis? Circulation 109(21 Suppl 1):II27–II33PubMed

36.

Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T (2001) Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 104(22):2673–2678CrossRefPubMed

37.

Channon KM, Guzik TJ (2002) Mechanisms of superoxide production in human blood vessels: relationship to endothelial dysfunction, clinical and genetic risk factors. J Physiol Pharmacol 53(4 Pt 1):515–524PubMed

38.

Schulte C, Zeller T (2015) microRNA-based diagnostics and therapy in cardiovascular disease—summing up the facts. Cardiovasc Diagn Ther 5(1):17–36. https://doi.org/10.3978/j.issn.2223-3652.2014.12.03 CrossRefPubMedPubMedCentral

39.

Zhang W, Yan L, Li Y, Chen W, Hu N, Wang H, Ou H (2015) Roles of miRNA-24 in regulating endothelial nitric oxide synthase expression and vascular endothelial cell proliferation. Mol Cell Biochem 405(1):281–289. https://doi.org/10.1007/s11010-015-2418-y CrossRefPubMed

40.

Ho JJ, Metcalf JL, Yan MS, Turgeon PJ, Wang JJ, Chalsev M, Petruzziello-Pellegrini TN, Tsui AK, He JZ, Dhamko H, Man HS, Robb GB, Teh BT, Ohh M, Marsden PA (2012) Functional importance of Dicer protein in the adaptive cellular response to hypoxia. J Biol Chem 287(34):29003–29020. https://doi.org/10.1074/jbc.M112.373365 CrossRefPubMedPubMedCentral

41.

Tokar T, Pastrello C, Rossos AEM, Abovsky M, Hauschild AC, Tsay M, Lu R, Jurisica I (2018) mirDIP 4.1-integrative database of human microRNA target predictions. Nucleic Acids Res 46(D1):D360-D370. https://doi.org/10.1093/nar/gkx1144 CrossRefPubMed

42.

Zhou BS, Ma RH, Si WX, Li SS, Xu Y, Tu X, Wang Q (2013) MicroRNA-503 targets FGF2 and VEGFA and inhibits tumor angiogenesis and growth. Cancer Lett 333(2):159–169. https://doi.org/10.1016/j.canlet.2013.01.028 CrossRefPubMed

43.

Zhang D, Shi Z, Li M, Mi J (2014) Hypoxia-induced miR-424 decreases tumor sensitivity to chemotherapy by inhibiting apoptosis. Cell Death Dis 5(6):e1301. https://doi.org/10.1038/Cddis.2014.240 CrossRefPubMedPubMedCentral

44.

Ghosh G, Subramanian IV, Adhikari N, Zhang X, Joshi HP, Basi D, Chandrashekhar YS, Hall JL, Roy S, Zeng Y, Ramakrishnan S (2010) Hypoxia-induced microRNA-424 expression in human endothelial cells regulates HIF-alpha isoforms and promotes angiogenesis. J Clin Investig 120(11):4141–4154. https://doi.org/10.1172/jci42980 CrossRefPubMedPubMedCentral

45.

Fasanaro P, D’Alessandra Y, Di Stefano V, Melchionna R, Romani S, Pompilio G, Capogrossi MC, Martelli F (2008) MicroRNA-210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine kinase ligand Ephrin-A3. J Biol Chem 283(23):15878–15883. https://doi.org/10.1074/jbc.M800731200 CrossRefPubMedPubMedCentral

46.

Voellenkle C, Rooij J, Guffanti A, Brini E, Fasanaro P, Isaia E, Croft L, David M, Capogrossi MC, Moles A, Felsani A, Martelli F (2012) Deep-sequencing of endothelial cells exposed to hypoxia reveals the complexity of known and novel microRNAs. RNA 18(3):472–484. https://doi.org/10.1261/rna.027615.111 CrossRefPubMedPubMedCentral

47.

Bavelloni A, Ramazzotti G, Poli A, Piazzi M, Focaccia E, Blalock W, Faenza I (2017) miRNA-210: a current overview. Anticancer Res 37(12):6511–6521. https://doi.org/10.21873/anticanres.12107 CrossRefPubMed

48.

Assumpcao MB, Moreira FC, Hamoy IG, Magalhaes L, Vidal A, Pereira A, Burbano R, Khayat A, Silva A, Santos S, Demachki S, Ribeiro-Dos-Santos A, Assumpcao P (2015) High-throughput miRNA sequencing reveals a field effect in gastric cancer and suggests an epigenetic network mechanism. Bioinform Biol Insights 9:111–117. https://doi.org/10.4137/BBI.S24066 CrossRefPubMedPubMedCentral

49.

Zhou J, Xu D, Xie H, Tang J, Liu R, Li J, Wang S, Chen X, Su J, Zhou X, Xia K, He Q, Chen J, Xiong W, Cao P, Cao K (2015) miR-33a functions as a tumor suppressor in melanoma by targeting HIF-1alpha. Cancer Biol Ther 16(6):846–855. https://doi.org/10.1080/15384047.2015.1030545 CrossRefPubMedPubMedCentral

50.

Meng W, Tai Y, Zhao H, Fu B, Zhang T, Liu W, Li H, Yang Y, Zhang Q, Feng Y, Chen G (2017) Downregulation of miR-33a-5p in hepatocellular carcinoma: a possible mechanism for chemotherapy resistance. Med Sci Monit 23:1295–1304CrossRefPubMedPubMedCentral

51.

Shou JJ, Gu SX, Gu WT (2015) Identification of dysregulated miRNAs and their regulatory signature in glioma patients using the partial least squares method. Exp Ther Med 9(1):167–171. https://doi.org/10.3892/etm.2014.2041 CrossRefPubMed

52.

Vidal-Gomez X, Perez-Cremades D, Mompeon A, Dantas AP, Novella S, Hermenegildo C (2018) MicroRNA as crucial regulators of gene expression in estradiol-treated human endothelial cells. Cell Physiol Biochem 45(5):1878–1892. https://doi.org/10.1159/000487910 CrossRefPubMed

53.

Zhou WY, Fong MY, Min YF, Somlo G, Liu L, Palomares MR, Yu Y, Chow A, O’Connor STF, Chin AR, Yen Y, Wang YF, Marcusson EG, Chu PG, Wu J, Wu XW, Li AX, Li Z, Gao HL, Ren XB, Boldin MP, Lin PC, Wang SE (2014) Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell 25(4):501–515. https://doi.org/10.1016/j.ccr.2014.03.007 CrossRefPubMedPubMedCentral

54.

Ma YS, Wu TM, Lv ZW, Lu GX, Cong XL, Xie RT, Yang HQ, Chang ZY, Sun R, Chai L, Cai MX, Zhong XJ, Zhu J, Fu D (2017) High expression of miR-105-1 positively correlates with clinical prognosis of hepatocellular carcinoma by targeting oncogene NCOA1. Oncotarget 8(7):11896–11905. https://doi.org/10.18632/oncotarget.14435 CrossRefPubMedPubMedCentral

55.

Guan YL, Chen L, Bao YJ, Li ZP, Cui R, Li GY, Wang YJ (2015) Identification of low miR-105 expression as a novel poor prognostic predictor for human glioma. Int J Clin Exp Med 8(7):10855–10864PubMedPubMedCentral

56.

Scheffer AR, Holdenrieder S, Kristiansen G, von Ruecker A, Muller SC, Ellinger J (2014) Circulating microRNAs in serum: novel biomarkers for patients with bladder cancer? World J Urol 32(2):353–358. https://doi.org/10.1007/s00345-012-1010-2 CrossRefPubMed

57.

Rhodes LV, Martin EC, Segar HC, Miller DFB, Buechlein A, Rusch DB, Nephew KP, Burow ME, Collins-Burow BM (2015) Dual regulation by microRNA-200b-3p and microRNA-200b-5p in the inhibition of epithelial-to-mesenchymal transition in triple-negative breast cancer. Oncotarget 6(18):16638–16652. doi:https://doi.org/10.18632/oncotarget.3184 CrossRefPubMedPubMedCentral

58.

Hudcova K, Raudenska M, Gumulec J, Binkova H, Horakova Z, Kostrica R, Babula P, Adam V, Masarik M (2016) Expression profiles of miR-29c, miR-200b and miR-375 in tumour and tumour-adjacent tissues of head and neck cancers. Tumor Biol 37(9):12627–12633. https://doi.org/10.1007/s13277-016-5147-2 CrossRef

59.

He HF, Tian W, Chen HL, Jiang K (2016) MiR-944 functions as a novel oncogene and regulates the chemoresistance in breast cancer. Tumor Biol 37(2):1599–1607. https://doi.org/10.1007/s13277-015-3844-x CrossRef

60.

Pan T, Chen WJ, Yuan XM, Shen J, Qin C, Wang LB (2017) miR-944 inhibits metastasis of gastric cancer by preventing the epithelial-mesenchymal transition via MACC1/Met/AKT signaling. FEBS Open Bio 7(7):905–914. https://doi.org/10.1002/2211-5463.12215 CrossRefPubMedPubMedCentral

61.

Wen LQ, Li YR, Jiang ZP, Zhang YC, Yang B, Han FH (2017) miR-944 inhibits cell migration and invasion by targeting MACC1 in colorectal cancer. Oncol Rep 37(6):3415–3422. https://doi.org/10.3892/or.2017.5611 CrossRefPubMed

62.

Yue J, Guan J, Wang X, Zhang L, Yang Z, Ao Q, Deng Y, Zhu P, Wang G (2013) MicroRNA-206 is involved in hypoxia-induced pulmonary hypertension through targeting of the HIF-1alpha/Fhl-1 pathway. Lab Investig 93(7):748–759. https://doi.org/10.1038/labinvest.2013.63 CrossRefPubMed

63.

Li L, Qiu XG, Lv PW, Wang F (2014) miR-639 promotes the proliferation and invasion of breast cancer cell in vitro. Cancer Cell Int 14(1):39. https://doi.org/10.1186/1475-2867-14-39 CrossRefPubMedPubMedCentral

64.

Lin ZY, Sun LJ, Chen WL, Liu BD, Wang YY, Fan S, Li YL, Li JS (2014) miR-639 regulates transforming growth factor beta-induced epithelial-mesenchymal transition in human tongue cancer cells by targeting FOXC1. Cancer Sci 105(10):1288–1298. https://doi.org/10.1111/cas.12499 CrossRefPubMedPubMedCentral

65.

Pu Q, Huang YC, Lu YR, Peng Y, Zhang J, Feng GL, Wang CG, Liu LX, Dai Y (2016) Tissue-specific and plasma microRNA profiles could be promising biomarkers of histological classification and TNM stage in non-small cell lung cancer. Thorac Cancer 7(3):348–354. https://doi.org/10.1111/1759-7714.12317 CrossRefPubMedPubMedCentral

66.

Zhao Z, Fan X, Jiang L, Xu Z, Xue L, Zhan Q, Song Y (2017) miR-503-3p promotes epithelial-mesenchymal transition in breast cancer by directly targeting SMAD2 and E-cadherin. J Genet Genomics 44(2):75–84. https://doi.org/10.1016/j.jgg.2016.10.005 CrossRefPubMed

67.

Chen L, Lu MH, Zhang D, Hao NB, Fan YH, Wu YY, Wang SM, Xie R, Fang DC, Zhang H, Hu CJ, Yang SM (2014) miR-1207-5p and miR-1266 suppress gastric cancer growth and invasion by targeting telomerase reverse transcriptase. Cell Death Dis 5(1):e1034. https://doi.org/10.1038/Cddis.2013.553 CrossRefPubMedPubMedCentral

68.

Matamala N, Vargas MT, Gonzalez-Campora R, Minambres R, Arias JI, Menendez P, Andres-Leon E, Gomez-Lopez G, Yanowsky K, Calvete-Candenas J, Inglada-Perez L, Martinez-Delgado B, Benitez J (2015) Tumor MicroRNA expression profiling identifies circulating MicroRNAs for early breast cancer detection. Clin Chem 61(8):1098–1106. https://doi.org/10.1373/clinchem.2015.238691 CrossRefPubMed

69.

Haldrup C, Kosaka N, Ochiya T, Borre M, Hoyer S, Orntoft TF, Sorensen KD (2014) Profiling of circulating microRNAs for prostate cancer biomarker discovery. Drug Deliv Transl Res 4(1):19–30. https://doi.org/10.1007/s13346-013-0169-4 CrossRefPubMed

70.

Nagy ZB, Bartak BK, Kalmar A, Galamb O, Wichmann B, Dank M, Igaz P, Tulassay Z, Molnar B (2017) Comparison of circulating miRNAs expression alterations in matched tissue and plasma samples during colorectal cancer progression. Pathol Oncol Res. https://doi.org/10.1007/s12253-017-0308-1 CrossRefPubMed

71.

Torres S, Garcia-Palmero I, Bartolome RA, Fernandez-Acenero MJ, Molina E, Calvino E, Segura MF, Casal JI (2017) Combined miRNA profiling and proteomics demonstrates that different miRNAs target a common set of proteins to promote colorectal cancer metastasis. J Pathol 242(1):39–51. https://doi.org/10.1002/path.4874 CrossRefPubMed

72.

Cui X, Li QY, He YK (2017) miR-3117 regulates hepatocellular carcinoma cell proliferation by targeting PHLPPL. Mol Cell Biochem 424(1–2):195–201. https://doi.org/10.1007/s11010-016-2855-2 CrossRefPubMed

73.

Neerincx M, Sie DLS, van de Wiel MA, van Grieken NCT, Burggraaf JD, Dekker H, Eijk PP, Ylstra B, Verhoef C, Meijer GA, Buffart TE, Verheul HMW (2015) MiR expression profiles of paired primary colorectal cancer and metastases by next-generation sequencing. Oncogenesis 4(10):e170. https://doi.org/10.1038/oncsis.2015.29 CrossRefPubMedPubMedCentral

74.

Jung CK, Jung SH, Yim SH, Jung JH, Choi HJ, Kang WK, Park SW, Oh ST, Kim JG, Lee SH, Chung YJ (2016) Predictive microRNAs for lymph node metastasis in endoscopically resectable submucosal colorectal cancer. Oncotarget 7(22):32902–32915. https://doi.org/10.18632/oncotarget.8766 CrossRefPubMedPubMedCentral

75.

Liu CL, Iqbal J, Teruya-Feldstein J, Shen YL, Dabrowska MJ, Dybkaer K, Lim MS, Piva R, Barreca A, Pellegrino E, Spaccarotella E, Lachel CM, Kucuk C, Jiang CS, Hu XZ, Bhagavathi S, Greiner TC, Weisenburger DD, Aoun P, Perkins SL, McKeithan TW, Inghirami G, Chan WC (2013) microRNA expression profiling identifies molecular signatures associated with anaplastic large cell lymphoma. Blood 122(12):2083–2092. https://doi.org/10.1182/blood-2012-08-447375 CrossRefPubMedPubMedCentral

76.

Sadeghi M, Ranjbar B, Ganjalikhany MR, Khan FM, Schmitz U, Wolkenhauer O, Gupta SK (2016) MicroRNA and transcription factor gene regulatory network analysis reveals key regulatory elements associated with prostate cancer progression. PLoS ONE 11(12):e0168760. https://doi.org/10.1371/journal.pone.0168760 CrossRefPubMedPubMedCentral

77.

Xiao W, Lou N, Ruan H, Bao L, Xiong Z, Yuan C, Tong J, Xu G, Zhou Y, Qu Y, Hu W, Gao Y, Ru Z, Liu L, Xiao H, Chen K, Yang H, Zhang X (2017) miR-144-3p promotes cell proliferation, metastasis, sunitinib resistance in clear cell renal cell carcinoma by downregulating ARID1A. Cell Physiol Biochem 43(6):2420–2433. https://doi.org/10.1159/000484395 CrossRefPubMed

78.

Liu C, Su C, Chen Y, Li G (2018) miR-144-3p promotes the tumor growth and metastasis of papillary thyroid carcinoma by targeting paired box gene 8. Cancer Cell Int 18:54. https://doi.org/10.1186/s12935-018-0550-y CrossRefPubMedPubMedCentral

79.

Coarfa C, Fiskus W, Eedunuri VK, Rajapakshe K, Foley C, Chew SA, Shah SS, Geng C, Shou J, Mohamed JS, O’Malley BW, Mitsiades N (2016) Comprehensive proteomic profiling identifies the androgen receptor axis and other signaling pathways as targets of microRNAs suppressed in metastatic prostate cancer. Oncogene 35(18):2345–2356. https://doi.org/10.1038/onc.2015.295 CrossRefPubMed

80.

Yang B, Jing C, Wang J, Guo X, Chen Y, Xu R, Peng L, Liu J, Li L (2014) Identification of microRNAs associated with lymphangiogenesis in human gastric cancer. Clin Transl Oncol 16(4):374–379. https://doi.org/10.1007/s12094-013-1081-6 CrossRefPubMed

81.

Zhang L, Qian JJ, Qiang Y, Huang HR, Wang CT, Li DM, Xu B (2014) Down-regulation of miR-4500 promoted non-small cell lung cancer growth. Cell Physiol Biochem 34(4):1166–1174. https://doi.org/10.1159/000366329 CrossRefPubMed

82.

Wu XZ, Gong ZD, Sun LY, Ma L, Wang QB (2017) MicroRNA-802 plays a tumour suppressive role in tongue squamous cell carcinoma through directly targeting MAP2K4. Cell Prolif 50(3):e12336. https://doi.org/10.1111/cpr.12336 CrossRefPubMedCentral

83.

Ma JJ, Hong L, Xu GH, Hao JF, Wang R, Guo H, Liu JQ, Zhang YJ, Nie YZ, Fan DM (2016) miR-483-3p plays an oncogenic role in esophageal squamous cell carcinoma by targeting tumor suppressor EI24. Cell Biol Int 40(4):448–455. https://doi.org/10.1002/cbin.10585 CrossRefPubMed

84.

Li M, Zhou Y, Xia T, Zhou X, Huang Z, Zhang H, Zhu W, Ding Q, Wang S (2018) Circulating microRNAs from the miR-106a-363 cluster on chromosome X as novel diagnostic biomarkers for breast cancer. Breast Cancer Res Treat. https://doi.org/10.1007/s10549-018-4757-3 CrossRefPubMedPubMedCentral

85.

Wang YW, Zhang WG, Ma R (2018) Bioinformatic identification of chemoresistance-associated microRNAs in breast cancer based on microarray data. Oncol Rep 39(3):1003–1010. https://doi.org/10.3892/or.2018.6205 CrossRefPubMedPubMedCentral

86.

Liu JP, Su Z, Zeng YJ, Zhang HY, Yang SL, Liu GJ (2017) miR-922 regulates CYLD expression and promotes the cell proliferation of human hepatocellular carcinoma. Oncol Rep 37(3):1445–1450. https://doi.org/10.3892/or.2017.5431 CrossRefPubMed

87.

Nawaz Z, Patil V, Thinagararjan S, Rao SA, Hegde AS, Arivazhagan A, Santosh V, Somasundaram K (2017) Impact of somatic copy number alterations on the glioblastoma miRNome: miR-4484 is a genomically deleted tumour suppressor. Mol Oncol 11(8):927–944. https://doi.org/10.1002/1878-0261.12060 CrossRefPubMedPubMedCentral

88.

Wang F, Lu J, Peng XH, Wang J, Liu X, Chen XM, Jiang YQ, Li XP, Zhang B (2016) Integrated analysis of microRNA regulatory network in nasopharyngeal carcinoma with deep sequencing. J Exp Clin Canc Res 35(1):17. https://doi.org/10.1186/s13046-016-0292-4 doi:ARTN 17.CrossRef

89.

Tian WJ, Wang GH, Liu YQ, Huang ZL, Zhang CQ, Ning K, Yu CX, Shen YJ, Wang MH, Li YT, Wang Y, Zhang BC, Zhao YR (2017) The miR-599 promotes non-small cell lung cancer cell invasion via SATB2. Biochem Bioph Res Commun 485(1):35–40. https://doi.org/10.1016/j.bbrc.2017.02.005 CrossRef

90.

Wang YH, Sui YN, Zhu QW, Sui XM (2017) Hsa-miR-599 suppresses the migration and invasion by targeting BRD4 in breast cancer. Oncol Lett 14(3):3455–3462. https://doi.org/10.3892/ol.2017.6651 CrossRefPubMedPubMedCentral

91.

van Beijnum JR, Giovannetti E, Poel D, Nowak-Sliwinska P, Griffioen AW (2017) miRNAs: micro-managers of anticancer combination therapies. Angiogenesis 20(2):269–285. https://doi.org/10.1007/s10456-017-9545-x CrossRefPubMedPubMedCentral

92.

Serocki M, Bartoszewska S, Janaszak-Jasiecka A, Ochocka RJ, Collawn JF, Bartoszewski R (2018) miRNAs regulate the HIF switch during hypoxia: a novel therapeutic target. Angiogenesis 21(2):183–202CrossRefPubMedPubMedCentral

Title: eNOS expression and NO release during hypoxia is inhibited by miR-200b in human endothelial cells
Authors: Anna Janaszak-Jasiecka
Anna Siekierzycka
Sylwia Bartoszewska
Marcin Serocki
Lawrence W. Dobrucki
James F. Collawn
Leszek Kalinowski
Rafal Bartoszewski
Publication date: 01-11-2018
Publisher: Springer Netherlands
Published in: Angiogenesis / Issue 4/2018
Print ISSN: 0969-6970
Electronic ISSN: 1573-7209
DOI: https://doi.org/10.1007/s10456-018-9620-y

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2018

Fluorescent reporter transgenic mice for in vivo live imaging of angiogenesis and lymphangiogenesis

Improved recovery from limb ischaemia by delivery of an affinity-isolated heparan sulphate

Targeting glioblastoma-derived pericytes improves chemotherapeutic outcome

Prion protein is essential for diabetic retinopathy-associated neovascularization

Gene therapy knockdown of VEGFR2 in retinal endothelial cells to treat retinopathy

Heparin impairs angiogenic signaling and compensatory lung growth after left pneumonectomy

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage