MicroRNA 199a and the eNOS (Endothelial NO Synthase)/NO Pathway
2018; Lippincott Williams & Wilkins; Volume: 38; Issue: 10 Linguagem: Inglês
10.1161/atvbaha.118.311515
ISSN1524-4636
Autores Tópico(s)Hydrogen's biological and therapeutic effects
ResumoHomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 38, No. 10MicroRNA 199a and the eNOS (Endothelial NO Synthase)/NO Pathway Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBMicroRNA 199a and the eNOS (Endothelial NO Synthase)/NO Pathway Nhat-Tu Le and Jun-ichi Abe Nhat-Tu LeNhat-Tu Le Nhat-Tu Le, PhD, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, Email E-mail Address: [email protected] From the Department of Cardiovascular Sciences (N.-T.L.), Houston Methodist Research Institute, TX and Jun-ichi AbeJun-ichi Abe Correspondence to Jun-ichi Abe, MD, PhD, Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, Email E-mail Address: [email protected] Department of Cardiology (J.-i.A.), The University of Texas MD Anderson Cancer Center, Houston. Originally published26 Sep 2018https://doi.org/10.1161/ATVBAHA.118.311515Arteriosclerosis, Thrombosis, and Vascular Biology. 2018;38:2278–2280This article is a commentary on the followingMicroRNA-199a-3p and MicroRNA-199a-5p Take Part to a Redundant Network of Regulation of the NOS (NO Synthase)/NO Pathway in the EndotheliumEndothelium-Derived NO and Endothelial Cell FunctionOne of the mechanisms endothelial cells (ECs) employ to maintain EC vascular homeostasis is releasing vasodilators such as NO.1 Exposure of ECs to pathological insults disrupts NO production and NO bioavailability2 that lead to EC dysfunction, setting the ground for atherosclerotic plaque formation and other cardiovascular diseases.3 In ECs, NO is mainly catalyzed by eNOS (endothelial NO synthase).4 Reduced NO production can be attributed to impaired eNOS activity, as eNOS expression increases rather than decreases during EC dysfunction, presumably because of elevated levels of hydrogen peroxide, a dismutation product of O2.−.5 Reduced NO bioavailability can be attributable to decreased NO production and increased NOS (NO synthase) degradation.6See accompanying article on page 2345Pathology of MiR-199a DysregulationMiR-199a-5p and miR-199a-3p are produced from 2 arms of a single molecule of miR-199a precursor.7 In ECs, miR-199a-5p acts as a potent regulator of angiogenesis.8,9 Inhibition of miR-199a-5p in human dermal microvascular ECs results in angiogenesis, whereas induction of miR-199a-5p inhibits angiogenic response in Matrigel culture. MiR-199a-5p negatively regulates angiogenic responses by directly targeting v-ets erythroblastosis virus E26 oncogene homolog 1 (Ets-1), thereby regulating the Ets-1-MMP1 (matrix metallopeptidase-1) pathway.9 Zheng et al10 described the role of miR-199a-5p in pulmonary microvascular EC proliferation, as miR-199a-5p delivery suppresses cell proliferation, whereas miR-199a-5p knockdown has an opposite effect. In ECs infected with human cytomegalovirus, miR-199a-5p expression is upregulated, leading to the enhanced cell migration and tube formation via downregulation of the SIRT1 (sirtuin-1)/eNOS pathway.11 MiR-199a is also involved in Fabry disease development and EC dysfunction.12,13Role of MiR-199a in NO Production in ECs and NO BioavailabilityIn this issue of the Journal of ATVB, Joris et al nicely demonstrate that both miR-199a-3p and miR-199a-5p are abundantly expressed in human and bovine aortic ECs and that human and bovine miR sequences are identical. The authors used bioinformatics tools to identify VEGFA (vascular endothelial growth factor A), calcineurin, and SOD1 (superoxide dismutase 1) as potential miR-199a-3p/-5p targets. In BAECs (bovine aortic endothelial cells) treated with a miR inhibitor LNA (locked nucleic acid), NO production increased by 2-fold, whereas expression of eNOS, DDAH1 (dimethylarginine dimethylaminohydrolase 1), PRMT1 (protein arginine methyltransferase 1), and the endogenous competitive substrate for eNOS remained unchanged. In contrast, treatment of BAECs with nonselective NOS inhibitor l-NAME (Nω-nitro-L-arginine methyl ester) decreased NO production to the basal level, whereas expression of eNOS regulators were unaffected. The authors reasoned that LNA-mediated miR-199a-3p/-5p inhibition promotes eNOS activity via Ser1177/Thr495 phosphorylation through upregulating the PI3K/Akt and calcineurin pathways and increases NO bioavailability by reducing O2− levels via increasing SOD1 expression. LNA-mediated miR-199a-3p/-5p inhibition also promotes VEGF (vascular endothelial growth factor)–mediated tube formation and improves vascular tone. To validate in vitro findings, they treated mice with antagomiRs and noted increased NO-dependent relaxation and eNOS-S1177 phosphorylation in aortas, as well as a decreased O2−. level in aortic rings, which correlated with higher circulating hemoglobin-NO in the venous blood along with greater expression of calcineurin and SOD1. These results suggest that inhibition of miR-199a-3p/-5p improves EC function. In the mouse model of angiotensin-mediated hypertension and cardiac hypertrophy, expression of both miR-199a-3p/-5p is induced in heart and aorta, whereas only miR-199a-5p is induced in plasma.14MiR-199a in ECs: How Much Do We Not Know?What has been known about miR biogenesis is that between the 2 RNA strands from the 2 arms of the DNA region, one strand is preferentially selected for entry into a silencing complex (mature, miR) whereas the other is degraded (immature, miR*). Lately, emerging evidence has revealed that some miRs* are functional and expressed abundantly.15 Both mature forms derived from the precursor miR-199a were identified in mice in 2003,16 and their expression was found in humans later.7,17 They were then renamed miR-199a-5p and miR-199a-3p.7,16,18–21 The miR-199a precursor is highly conserved across species, suggesting that miR-199a-5p and miR-199a-3p possess important biological functions.7 Whereas the role of miR-199a in cancer as well as in cardiomyocyte apoptosis have been studied extensively, its function in EC biology remains to be characterized. In the present study, Joris et al found that miR-199a-5p and miR-199a-3p are highly expressed in both human and bovine ECs. Their studies have revealed that miR-199a-5p and miR-199a-3p play independent roles in EC dysfunction via the regulation of NO production and bioavailability. Inhibition of miR-199a-3p and miR-199a-5p independently increases NO bioavailability via inducing eNOS enzymatic activity and reducing NO degradation. Consequently, VEGF-mediated tube formation by ECs is promoted, and contractile tone is improved.The present study has broadened the biological spectrum of miR-199a functions from cancer biology, cardiomyocyte apoptosis, and heart failure to EC dysfunction and vascular homeostasis. Why and how important both mature forms derived from the same miR-199a precursor are required in the regulation of NO production and bioavailability is unknown. With the current knowledge on miR-199a function in ECs, further studies are necessary to gain deeper insights into pathological implications of miR-199a (Figure). First, NO is produced when ECs are exposed to mechanical forces including hemodynamic shear stress and intraluminal pressure that trigger biochemical signaling involving multiple enzymes and mechanosensors, ultimately leading to eNOS activation.22 Several mechanosensors are identified to initiate signal transduction in ECs such as mechanosensing ion channels, G-protein–coupled receptors, integrins-transmembrane receptors.23–26 Therefore, it is plausible to examine potential roles for miR-199a-5p and miR-199a-3p in shear-induced NO production and whether they are regulated by mechanosensors. Second, although miR-199a is encoded by 2 loci within 2 different introns on dynamin 2 and 3, miR-199a-1 is on chromosome 19 of dynamin 2 (intron 15), whereas miR-199a-2 is on chromosome 1 of dynamin 3 (intron 14), but there is no reported data showing that the expression of miR-199a precursors is regulated by dynamin genes, indicating that miR-199a precursors can be regulated by their own promoters.7 Additionally, it is well known that miR-targeting LNA has high affinity to the target sequence, but miR-targeting LNA treatment might also result in offtarget effects including altering gene expression in neighbor tissues.27 Hence, to determine molecular mechanisms by which the expression of miR-199a in ECs is regulated, as well as how miR-199a-5p and miR-199a-3p are differently regulated, should provide us with a better approach in the prevention of their pathology. Third, because circulating miRs can be detected in different fluid compartments such as blood, saliva, and urine, it is possible that miR-199a-5p and miR-199a-3p expression can be a harbinger of various coronary artery disease stages from subclinical atherosclerotic disease.28 Thus, linking miR-199a-5p and miR-199a-3p to atherosclerotic disease burden as primarily diagnostic markers could help us to define their prognostic significance in coronary artery disease. Another limitation in the current study is the use of bovine aortic ECs, which lack miR-199a-3p, and therefore significantly limits our understanding of the functional difference between miR-199a-5p and miR-199a-3p.Download figureDownload PowerPointFigure. MiR-199a-3p and miR-199a-5p coordinately regulate NO bioavailability via inhibiting antioxidants expression and eNOS (endothelial NO synthase) phosphorylation. It remains unclear how miR-199a-3p and miR-199a-5p expression are modulated by proatherogenic and antiatherogenic stimuli (including NO itself).AcknowledgmentsWe thank Dr Keigi Fujiwara for discussions and critical reading of the manuscript.Sources of FundingOur research activities are supported by grants from the National Institute of Health (NIH) to N.-T. Le (HL-134740) and J.-i. Abe (HL-130193, HL-123346, and HL-118462).DisclosuresNone.FootnotesCorrespondence to Jun-ichi Abe, MD, PhD, Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, Email [email protected]orgNhat-Tu Le, PhD, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, Email [email protected]orgReferences1. Sandoo A, van Zanten JJ, Metsios GS, Carroll D, Kitas GD. The endothelium and its role in regulating vascular tone.Open Cardiovasc Med J. 2010; 4:302–312. doi: 10.2174/1874192401004010302CrossrefMedlineGoogle Scholar2. Tousoulis D, Kampoli AM, Tentolouris C, Papageorgiou N, Stefanadis C. The role of nitric oxide on endothelial function.Curr Vasc Pharmacol. 2012; 10:4–18.CrossrefMedlineGoogle Scholar3. Mudau M, Genis A, Lochner A, Strijdom H. Endothelial dysfunction: the early predictor of atherosclerosis.Cardiovasc J Afr. 2012; 23:222–231. doi: 10.5830/CVJA-2011-068CrossrefMedlineGoogle Scholar4. Förstermann U, Sessa WC. Nitric oxide synthases: regulation and function.Eur Heart J. 2012; 33:829, 837a–837, 837a. doi: 10.1093/eurheartj/ehr304CrossrefGoogle Scholar5. Yang Z, Ming XF. Recent advances in understanding endothelial dysfunction in atherosclerosis.Clin Med Res. 2006; 4:53–65.CrossrefMedlineGoogle Scholar6. Zhao Y, Vanhoutte PM, Leung SW. Vascular nitric oxide: beyond eNOS.J Pharmacol Sci. 2015; 129:83–94. doi: 10.1016/j.jphs.2015.09.002CrossrefMedlineGoogle Scholar7. Gu S, Chan WY. Flexible and versatile as a chameleon-sophisticated functions of microRNA-199a.Int J Mol Sci. 2012; 13:8449–8466. doi: 10.3390/ijms13078449CrossrefMedlineGoogle Scholar8. Dai L, Lou W, Zhu J, Zhou X, Di W. MiR-199a inhibits the angiogenic potential of endometrial stromal cells under hypoxia by targeting HIF-1α/VEGF pathway.Int J Clin Exp Pathol. 2015; 8:4735–4744.MedlineGoogle Scholar9. Chan YC, Roy S, Huang Y, Khanna S, Sen CK. The microRNA miR-199a-5p down-regulation switches on wound angiogenesis by derepressing the v-ets erythroblastosis virus E26 oncogene homolog 1-matrix metalloproteinase-1 pathway.J Biol Chem. 2012; 287:41032–41043. doi: 10.1074/jbc.M112.413294CrossrefMedlineGoogle Scholar10. Zheng L, Xing L, Zeng C, Wu T, Gui Y, Li W, Lan T, Yang Y, Gu Q, Qi C, Zhang Q, Tang F, He X, Wang L. Inactivation of PI3Kδ induces vascular injury and promotes aneurysm development by upregulating the AP-1/MMP-12 pathway in macrophages.Arterioscler Thromb Vasc Biol. 2015; 35:368–377. doi: 10.1161/ATVBAHA.114.304365LinkGoogle Scholar11. Zhang S, Liu L, Wang R, Tuo H, Guo Y, Yi L, Wang J, Wang D. MiR-199a-5p promotes migration and tube formation of human cytomegalovirus-infected endothelial cells through downregulation of SIRT1 and eNOS.Arch Virol. 2013; 158:2443–2452. doi: 10.1007/s00705-013-1744-1CrossrefMedlineGoogle Scholar12. Cammarata G, Scalia S, Colomba P, Zizzo C, Pisani A, Riccio E, Montalbano M, Alessandro R, Giordano A, Duro G. A pilot study of circulating microRNAs as potential biomarkers of Fabry disease.Oncotarget. 2018; 9:27333–27345. doi: 10.18632/oncotarget.25542CrossrefMedlineGoogle Scholar13. Keßler J, Rot S, Bache M, Kappler M, Würl P, Vordermark D, Taubert H, Greither T. miR-199a-5p regulates HIF-1α and OSGIN2 and its expression is correlated to soft-tissue sarcoma patients' outcome.Oncol Lett. 2016; 12:5281–5288. doi: 10.3892/ol.2016.5320CrossrefMedlineGoogle Scholar14. Joris V, Leon Gomez E, Menchi L, Lobysheva I, Di Mauro V, Esfahani H, Condorelli G, Balligand J-L, Catalucci D, Dessy C. MicroRNA-199a-3p and microRNA-199a-5p take part to a redundant network of regulation of the NOS (NO synthase)/NO pathway in the endothelium.Arterioscler Thromb Vasc Biol. 2018; 38:2345–2357. doi: 10.1161/ATVBAHA.118.311145LinkGoogle Scholar15. Guo L, Lu Z. The fate of miRNA* strand through evolutionary analysis: implication for degradation as merely carrier strand or potential regulatory molecule?PLoS One. 2010; 5:e11387. doi: 10.1371/journal.pone.0011387CrossrefMedlineGoogle Scholar16. Lagos-Quintana M, Rauhut R, Meyer J, Borkhardt A, Tuschl T. New microRNAs from mouse and human.RNA. 2003; 9:175–179.CrossrefMedlineGoogle Scholar17. Kozomara A, Griffiths-Jones S. miRBase: annotating high confidence microRNAs using deep sequencing data.Nucleic Acids Res. 2014; 42(Database issue):D68–D73. doi: 10.1093/nar/gkt1181CrossrefMedlineGoogle Scholar18. Kozomara A, Griffiths-Jones S. miRBase: integrating microRNA annotation and deep-sequencing data.Nucleic Acids Res. 2011; 39(Database issue):D152–D157. doi: 10.1093/nar/gkq1027CrossrefMedlineGoogle Scholar19. Krichevsky AM, Gabriely G. miR-21: a small multi-faceted RNA.J Cell Mol Med. 2009; 13:39–53. doi: 10.1111/j.1582-4934.2008.00556.xCrossrefMedlineGoogle Scholar20. Lim LP, Glasner ME, Yekta S, Burge CB, Bartel DP. Vertebrate microRNA genes.Science. 2003; 299:1540. doi: 10.1126/science.1080372CrossrefMedlineGoogle Scholar21. Landgraf P, Rusu M, Sheridan R, et al. A mammalian microRNA expression atlas based on small RNA library sequencing.Cell. 2007; 129:1401–1414. doi: 10.1016/j.cell.2007.04.040CrossrefMedlineGoogle Scholar22. Sriram K, Laughlin JG, Rangamani P, Tartakovsky DM. Shear-induced nitric oxide production by endothelial cells.Biophys J. 2016; 111:208–221. doi: 10.1016/j.bpj.2016.05.034CrossrefMedlineGoogle Scholar23. Becker CF, Strop P, Bass RB, Hansen KC, Locher KP, Ren G, Yeager M, Rees DC, Kochendoerfer GG. Conversion of a mechanosensitive channel protein from a membrane-embedded to a water-soluble form by covalent modification with amphiphiles.J Mol Biol. 2004; 343:747–758. doi: 10.1016/j.jmb.2004.08.062CrossrefMedlineGoogle Scholar24. Chachisvilis M, Zhang YL, Frangos JA. G protein-coupled receptors sense fluid shear stress in endothelial cells.Proc Natl Acad Sci USA. 2006; 103:15463–15468. doi: 10.1073/pnas.0607224103CrossrefMedlineGoogle Scholar25. Shyy JY, Chien S. Role of integrins in endothelial mechanosensing of shear stress.Circ Res. 2002; 91:769–775.LinkGoogle Scholar26. Johnson BD, Mather KJ, Wallace JP. Mechanotransduction of shear in the endothelium: basic studies and clinical implications.Vasc Med. 2011; 16:365–377. doi: 10.1177/1358863X11422109CrossrefMedlineGoogle Scholar27. Krützfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, Stoffel M. Silencing of microRNAs in vivo with 'antagomirs'.Nature. 2005; 438:685–689. doi: 10.1038/nature04303CrossrefMedlineGoogle Scholar28. Feinberg MW, Moore KJ. MicroRNA regulation of atherosclerosis.Circ Res. 2016; 118:703–720. doi: 10.1161/CIRCRESAHA.115.306300LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Santos E, Melo G, Santana P, Quadros I, Yahouédéhou S, Guarda C, Santiago R, Fiuza L, Carvalho S, Adorno E, Kaneto C, Fonseca T, Goncalves M and Aleluia M (2022) A Description of the Hemolytic Component in Sickle Leg Ulcer: The Role of Circulating miR-199a-5p, miR-144, and miR-126, Biomolecules, 10.3390/biom12020317, 12:2, (317) Related articlesMicroRNA-199a-3p and MicroRNA-199a-5p Take Part to a Redundant Network of Regulation of the NOS (NO Synthase)/NO Pathway in the EndotheliumVirginie Joris, et al. Arteriosclerosis, Thrombosis, and Vascular Biology. 2018;38:2345-2357 October 2018Vol 38, Issue 10 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.118.311515PMID: 30354226 Originally publishedSeptember 26, 2018 PDF download Advertisement SubjectsCell Signaling/Signal TransductionEndothelium/Vascular Type/Nitric OxideVascular Biology
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