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Volume 17, Issue 1
  • ISSN: 1874-4672
  • E-ISSN: 1874-4702
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Abstract

Aims:

The aim of this study was to develop a possible treatment for pulmonary arterial hypertension.

Background:

Pulmonary arterial hypertension (PAH) is a rare disease characterised by a pulmonary arterial pressure greater than 20 mmHg. One of the factors that contribute to PAH is an increase in the production of endothelin-1, a polypeptide that increases vascular resistance in the pulmonary arteries, leading to increased pulmonary arterial pressure and right ventricular hypertrophy.

Objective:

The objective of this study was to design, synthesize, and evaluate two siRNAs directed against endothelin-1 in a rat model of PAH induced with monocrotaline.

Methods:

Wistar rats were administered monocrotaline (60 mg/kg) to induce a PAH model. Following two weeks of PAH evolution, the siRNAs were administered, and after two weeks, right ventricular hypertrophy was evaluated using the RV/LV+S ratio, blood pressure, weight, and relative expression of ECE-1 (Endothelin-converting enzyme-1) mRNA (messenger RNA) by RT-PCR (real-time PCR).

Results:

The monocrotaline group showed an increase in the hypertrophy index and in ECE-1 mRNA, as well as a significant decrease in weight compared to the control group, while in the monocrotaline + siRNA group, a significant decrease was observed in the relative expression of ECE-1 mRNA, as well as in right ventricular hypertrophy.

Conclusions:

Based on the above information, we conclude that the administration of siRNAs directed to ECE-1 decreases the damage associated with PAH.

© 2024 The Author(s). Published by Bentham Science Publisher.
This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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2024-03-08
2024-11-22

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References

  1. RuoppN.F. CockrillB.A. Diagnosis and treatment of pulmonary arterial hypertension.JAMA2022327141379139110.1001/jama.2022.440235412560
     [Google Scholar]
  2. SimonneauG. MontaniD. CelermajerD.S. DentonC.P. GatzoulisM.A. KrowkaM. WilliamsP.G. SouzaR. Haemodynamic definitions and updated clinical classification of pulmonary hypertension.Eur. Respir. J.2019531180191310.1183/13993003.01913‑201830545968
     [Google Scholar]
  3. DodsonM.W. BrownL.M. ElliottC.G. Pulmonary arterial hypertension.Heart Fail. Clin.201814325526910.1016/j.hfc.2018.02.00329966625
     [Google Scholar]
  4. BeshayS. SahayS. HumbertM. Evaluation and management of pulmonary arterial hypertension.Respir. Med.202017110609910.1016/j.rmed.2020.10609932829182
     [Google Scholar]
  5. BourgeoisA. OmuraJ. HabboutK. BonnetS. BoucheratO. Pulmonary arterial hypertension: New pathophysiological insights and emerging therapeutic targets.Int. J. Biochem. Cell Biol.201810491310.1016/j.biocel.2018.08.01530189252
     [Google Scholar]
  6. ZhangZ. ZhuS. WangM. WangX. TongX. WanJ. DingJ. New progress in diagnosis and treatment of pulmonary arterial hypertension.J. Cardiothorac. Surg.20221721610.1186/s13019‑022‑01947‑y36038916
     [Google Scholar]
  7. StewartD.J. LevyR.D. CernacekP. LanglebenD. Increased plasma endothelin-1 in pulmonary hypertension: Marker or mediator of disease?Ann. Intern. Med.1991114646446910.7326/0003‑4819‑114‑6‑4641994793
     [Google Scholar]
  8. LüscherT.F. TannerF.C. Endothelial regulation of vascular tone and growth.Am. J. Hypertens.199367_Pt_2283S293S10.1093/ajh/6.7.283S8398013
     [Google Scholar]
  9. HaynesW.G. WebbD.J. Endothelium-dependent modulation of responses to endothelin-I in human veins.Clin. Sci.199384442743310.1042/cs08404278482047
     [Google Scholar]
  10. MaguireJ.J. DavenportA.P. ET A receptor-mediated constrictor responses to endothelin peptides in human blood vessels in vitro.Br. J. Pharmacol.1995115119119710.1111/j.1476‑5381.1995.tb16338.x7647976
     [Google Scholar]
  11. IijimaK. LinL. NasjlettiA. GoligorskyM.S. Intracellular signaling pathway of endothelin-1.J. Cardiovasc. Pharmacol.199117Suppl. 7S146S14910.1097/00005344‑199100177‑000401725313
     [Google Scholar]
  12. TakahashiM. MatsushitaY. IijimaY. TanzawaK. Purification and characterization of endothelin-converting enzyme from rat lung.J. Biol. Chem.199326828213942139810.1016/S0021‑9258(19)36936‑48407980
     [Google Scholar]
  13. XuD. EmotoN. GiaidA. SlaughterC. KawS. deWitD. YanagisawaM. ECE-1: A membrane-bound metalloprotease that catalyzes the proteolytic activation of big endothelin-1.Cell199478347348510.1016/0092‑8674(94)90425‑18062389
     [Google Scholar]
  14. SchweizerA. ValdenaireO. NelböckP. DeuschleU. Dumas Milne EdwardsJ.B. StumpfJ.G. LöfflerB.M. Human endothelin-converting enzyme (ECE-1): Three isoforms with distinct subcellular localizations.Biochem. J.1997328387187710.1042/bj32808719396733
     [Google Scholar]
  15. ValdenaireO. Lepailleur-EnoufD. EgidyG. ThouardA. BarretA. VranckxR. TougardC. MichelJ.B. A fourth isoform of endothelin‐converting enzyme (ECE-1) is generated from an additional promoter.Eur. J. Biochem.1999264234134910.1046/j.1432‑1327.1999.00602.x10491078
     [Google Scholar]
  16. GiaidA. Nitric oxide and endothelin-1 in pulmonary hypertension.Chest1998114S3208S212S10.1378/chest.114.3_Supplement.208S9741571
     [Google Scholar]
  17. XuW. JanochaA.J. ErzurumS.C. Metabolism in pulmonary hypertension.Annu. Rev. Physiol.202183155157610.1146/annurev‑physiol‑031620‑12395633566674
     [Google Scholar]
  18. ZhangT. KawaguchiN. YoshiharaK. HayamaE. FurutaniY. KawaguchiK. TanakaT. NakanishiT. Silibinin efficacy in a rat model of pulmonary arterial hypertension using monocrotaline and chronic hypoxia.Respir. Res.20192017910.1186/s12931‑019‑1041‑y31023308
     [Google Scholar]
  19. CulleyM.K. ChanS.Y. Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains.J. Clin. Invest.201812893704371510.1172/JCI12084730080181
     [Google Scholar]
  20. KayJ.M. SmithP. HeathD. WillJ.A. Effects of phenobarbitone, cinnarizine, and zoxazolamine on the development of right ventricular hypertrophy and hypertensive pulmonary vascular disease in rats treated with monocrotaline.Cardiovasc. Res.197610220020510.1093/cvr/10.2.200132989
     [Google Scholar]
  21. XiaoR. SuY. FengT. SunM. LiuB. ZhangJ. LuY. LiJ. WangT. ZhuL. HuQ. Monocrotaline induces endothelial injury and pulmonary hypertension by targeting the extracellular calcium-sensing receptor.J. Am. Heart Assoc.201764e00486510.1161/JAHA.116.00486528330842
     [Google Scholar]
  22. GhodsiF. WillJ.A. Changes in pulmonary structure and function induced by monocrotaline intoxication.Am. J. Physiol. Heart Circ. Physiol.19812402H149H15510.1152/ajpheart.1981.240.2.H1496451183
     [Google Scholar]
  23. MitraA. GhoshR.K. BandyopadhyayD. GhoshG.C. KalraA. LavieC.J. Significance of pulmonary hypertension in hypertrophic cardiomyopathy.Curr. Probl. Cardiol.202045610039810.1016/j.cpcardiol.2018.10.00230497690
     [Google Scholar]
  24. KatoT. KitamuraH. KanisawaM. Comparative effects of isosorbide dinitrate, prednisolone, indomethacin, and elastase on the development of monocrotaline-induced pulmonary hypertension.Exp. Mol. Pathol.198950330331510.1016/0014‑4800(89)90040‑32498122
     [Google Scholar]
  25. YanY. LiuX.Y. LuA. WangX.Y. JiangL.X. WangJ.C. Non-viral vectors for RNA delivery.J. Control. Release202234224127910.1016/j.jconrel.2022.01.00835016918
     [Google Scholar]
  26. BertrandJ.R. PottierM. VekrisA. OpolonP. MaksimenkoA. MalvyC. Comparison of antisense oligonucleotides and siRNAs in cell culture and in vivo.Biochem. Biophys. Res. Commun.200229641000100410.1016/S0006‑291X(02)02013‑212200148
     [Google Scholar]
  27. LuoK.Q. ChangD.C. The gene-silencing efficiency of siRNA is strongly dependent on the local structure of mRNA at the targeted region.Biochem. Biophys. Res. Commun.2004318130331010.1016/j.bbrc.2004.04.02715110788
     [Google Scholar]
  28. ZamoreP.D. TuschlT. SharpP.A. BartelD.P. RNAi.Cell20001011253310.1016/S0092‑8674(00)80620‑010778853
     [Google Scholar]
  29. FireA. XuS. MontgomeryM.K. KostasS.A. DriverS.E. MelloC.C. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans.Nature1998391666980681110.1038/358889486653
     [Google Scholar]
  30. RivasF.V. ToliaN.H. SongJ.J. AragonJ.P. LiuJ. HannonG.J. Joshua-TorL. Purified Argonaute2 and an siRNA form recombinant human RISC.Nat. Struct. Mol. Biol.200512434034910.1038/nsmb91815800637
     [Google Scholar]
  31. KielyD.G. LawrieA. HumbertM. Screening strategies for pulmonary arterial hypertension.Eur. Heart J. Suppl.201921K9K2010.1093/eurheartj/suz20431857796
     [Google Scholar]
  32. HoudeM. DesbiensL. D’Orléans-JusteP. Endothelin-1.Adv. Pharmacol.20167714317510.1016/bs.apha.2016.05.00227451097
     [Google Scholar]
  33. MiyauchiT. YorikaneR. SakaiS. SakuraiT. OkadaM. NishikibeM. YanoM. YamaguchiI. SugishitaY. GotoK. Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension.Circ. Res.199373588789710.1161/01.RES.73.5.8878403258
     [Google Scholar]
  34. TaiW. Chemical modulation of siRNA lipophilicity for efficient delivery.J. Control. Release20193079810710.1016/j.jconrel.2019.06.02231229473
     [Google Scholar]
  35. TaiW. Current aspects of siRNA bioconjugate for in vitro and in vivo delivery.Molecules2019b2412221110.3390/molecules2412221131200490
     [Google Scholar]
  36. GilleronJ. QuerbesW. ZeigererA. BorodovskyA. MarsicoG. SchubertU. ManygoatsK. SeifertS. AndreeC. StöterM. Epstein-BarashH. ZhangL. KotelianskyV. FitzgeraldK. FavaE. BickleM. KalaidzidisY. AkincA. MaierM. ZerialM. Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape.Nat. Biotechnol.201331763864610.1038/nbt.261223792630
     [Google Scholar]
  37. WittrupA. AiA. LiuX. HamarP. TrifonovaR. CharisseK. ManoharanM. KirchhausenT. LiebermanJ. Visualizing lipid-formulated siRNA release from endosomes and target gene knockdown.Nat. Biotechnol.201533887087610.1038/nbt.329826192320
     [Google Scholar]
  38. RahimiP. MobarakehV.I. KamalzareS. SajadianFardF. VahabpourR. ZabihollahiR. Comparison of transfection efficiency of polymer-based and lipid-based transfection reagents.Bratisl. Med. J.20181191170170510.4149/BLL_2018_12530686003
     [Google Scholar]
  39. ShahbaziS. HaghighipourN. SoleymaniS. NadjiS.A. BolhassaniA. Delivery of molecular cargoes in normal and cancer cell lines using non-viral delivery systems.Biotechnol. Lett.201840692393110.1007/s10529‑018‑2551‑229633093
     [Google Scholar]
  40. National Center for Biotechnology InformationHomo sapiens ECE1 gene for endothelin converting enzyme 1, complete cds.2024Available from: https://www.ncbi.nlm.nih.gov/nuccore/?term=Homo+sapiens+ECE1
  41. European Bioinformatics InstituteEMBOSS Tools.2024EMBOSS Tools.Available from: https://www.ebi.ac.uk/Tools/emboss/
    [Google Scholar]
  42. University of ViennaRNAfold.2024Available from: http://rna.tbi.univie.ac.at/cgi-bin/RNAWebSuite/RNAfold.cgi
/content/journals/cmp/10.2174/0118761429283384240226074921
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siRNA Targeting ECE-1 Partially Reverses Pulmonary Arterial Hypertension-associated Damage in a Monocrotaline Model
Curr Mol Pharmacol 17, e18761429283384 (2024); https://doi.org/10.2174/0118761429283384240226074921
/content/journals/cmp/10.2174/0118761429283384240226074921
/content/journals/cmp/10.2174/0118761429283384240226074921
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  • Article Type:     Research Article
Keyword(s): Endothelin-1; Endothelin-1 converting enzyme; Monocrotaline; Pulmonary arterial hypertension; Small interfering RNA

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