Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Current Molecular Medicine
  4. Volume 25, Issue 1
  5. Article
Volume 25, Issue 1
  • ISSN: 1566-5240
  • E-ISSN: 1875-5666

Abstract

Background

Heart failure (HF) is the ultimate transformation result of various cardiovascular diseases. Mitochondria-mediated cardiomyocyte apoptosis has been uncovered to be associated with this disorder.

Objective

This study mainly delves into the mechanism of the anti-arrhythmic drug amiodarone on mitochondrial toxicity of cardiomyocytes.

Methods

The viability of H9c2 cells treated with amiodarone at 0.5, 1, 2, 3, and 4 μM was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and Sigmar1 expression was examined by quantitative real-time PCR (qRT-PCR). After transfection, the viability, apoptosis, reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP), and potassium voltage-gated channel subfamily H member 2 (KCNH2) expression in H9c2 cells were assessed by MTT, flow cytometry, ROS assay kit, mitochondria staining kit, and Western blot.

Results

Amiodarone at 1-4 μM notably weakened H9c2 cell viability with IC value of 2.62 ± 0.43 μM. Amiodarone at 0.5-4 μM also evidently suppressed the Sigmar1 level in H9c2 cells. Amiodarone repressed H9c2 cell viability and KCNH2 level and triggered apoptosis, ROS production and mitochondrial depolarization, while Sigmar1 up-regulation reversed its effects. Moreover, KCNH2 silencing neutralized the effect of Sigmar1 up-regulation on H9c2 cell viability, apoptosis, and ROS production.

Conclusion

Amiodarone facilitates the apoptosis of H9c2 cells by restraining Sigmar1 expression and blocking KCNH2-related potassium channels.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cmm/10.2174/0115665240265771231129105108
2024-01-08
2025-01-19

  • From This Site

    /content/journals/cmm/10.2174/0115665240265771231129105108
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. AlvarezC.K. CroninE. BakerW.L. KlugerJ. Heart failure as a substrate and trigger for ventricular tachycardia.J. Interv. Card. Electrophysiol.201956322924710.1007/s10840‑019‑00623‑x
     [Google Scholar]
  2. CooperT.J. ClelandJ.G.F. GuazziM. Effects of sildenafil on symptoms and exercise capacity for heart failure with reduced ejection fraction and pulmonary hypertension (the SilHF study): A randomized placebo‐controlled multicentre trial.Eur. J. Heart Fail.20222471239124810.1002/ejhf.2527 35596935
     [Google Scholar]
  3. OmoteK. VerbruggeF.H. BorlaugB.A. Heart failure with preserved ejection fraction: Mechanisms and treatment strategies.Annu. Rev. Med.202273132133710.1146/annurev‑med‑042220‑022745 34379445
     [Google Scholar]
  4. PalauP. AmiguetM. DomínguezE. Short‐term effects of dapagliflozin on maximal functional capacity in heart failure with reduced ejection fraction (DAPA‐VO2): A randomized clinical trial.Eur. J. Heart Fail.202224101816182610.1002/ejhf.2560 35604416
     [Google Scholar]
  5. KangP.M. IzumoS. Apoptosis in heart: Basic mechanisms and implications in cardiovascular diseases.Trends Mol. Med.20039417718210.1016/S1471‑4914(03)00025‑X 12727144
     [Google Scholar]
  6. PezelT. ViallonM. CroisilleP. Imaging interstitial fibrosis, left ventricular remodeling, and function in stage A and B heart failure.JACC Cardiovasc. Imaging20211451038105210.1016/j.jcmg.2020.05.036 32828781
     [Google Scholar]
  7. ZhangN. FengB. MaX. SunK. XuG. ZhouY. Dapagliflozin improves left ventricular remodeling and aorta sympathetic tone in a pig model of heart failure with preserved ejection fraction.Cardiovasc. Diabetol.201918110710.1186/s12933‑019‑0914‑1 31429767
     [Google Scholar]
  8. YamadaS. ArrellD.K. RosenowC.S. BartunekJ. BehfarA. TerzicA. Ventricular remodeling in ischemic heart failure stratifies responders to stem cell therapy.Stem Cells Transl. Med.202091747910.1002/sctm.19‑0149 31373782
     [Google Scholar]
  9. LiG. ShaoY. GuoH.C. MicroRNA-27b-3p down-regulates FGF1 and aggravates pathological cardiac remodelling.Cardiovasc. Res.202211892139215110.1093/cvr/cvab248 34358309
     [Google Scholar]
  10. BraunwaldE. Heart failure.JACC Heart Fail.20131112010.1016/j.jchf.2012.10.002 24621794
     [Google Scholar]
  11. WongN.R. MohanJ. KopeckyB.J. Resident cardiac macrophages mediate adaptive myocardial remodeling.Immunity202154920722088.e710.1016/j.immuni.2021.07.003 34320366
     [Google Scholar]
  12. Valiente-AlandiI. PotterS.J. SalvadorA.M. Inhibiting fibronectin attenuates fibrosis and improves cardiac function in a model of heart failure.Circulation2018138121236125210.1161/CIRCULATIONAHA.118.034609 29653926
     [Google Scholar]
  13. GaoG. ChenW. YanM. Rapamycin regulates the balance between cardiomyocyte apoptosis and autophagy in chronic heart failure by inhibiting mTOR signaling.Int. J. Mol. Med.2020451195209 31746373
     [Google Scholar]
  14. WangS.H. TsaiK.L. ChouW.C. Quercetin mitigates cisplatin-induced oxidative damage and apoptosis in cardiomyocytes through Nrf2/HO-1 signaling pathway.Am. J. Chin. Med.20225051281129810.1142/S0192415X22500537 35670059
     [Google Scholar]
  15. ShiY. ZhangZ. YinQ. Cardiac‐specific overexpression of miR‐122 induces mitochondria‐dependent cardiomyocyte apoptosis and promotes heart failure by inhibiting Hand2.J. Cell. Mol. Med.202125115326533410.1111/jcmm.16544 33942477
     [Google Scholar]
  16. BossuytJ. BorstJ.M. VerberckmoesM. BaileyL.R.J. BersD.M. HegyiB. Protein kinase D1 regulates cardiac hypertrophy, potassium channel remodeling, and arrhythmias in heart failure.J. Am. Heart Assoc.20221119e02757310.1161/JAHA.122.027573 36172952
     [Google Scholar]
  17. LeeC.H. ScheinmanM.M. “Short” also matters.Heart Rhythm20232081197119810.1016/j.hrthm.2023.02.026 37517862
     [Google Scholar]
  18. SanguinettiM.C. Tristani-FirouziM. hERG potassium channels and cardiac arrhythmia.Nature2006440708346346910.1038/nature04710 16554806
     [Google Scholar]
  19. NussH.B. MarbánE. JohnsD.C. Overexpression of a human potassium channel suppresses cardiac hyperexcitability in rabbit ventricular myocytes.J. Clin. Invest.1999103688989610.1172/JCI5073 10079110
     [Google Scholar]
  20. SyrenP. RahmA.K. SchweizerP.A. Histone deacetylase 2-dependent ventricular electrical remodeling in a porcine model of early heart failure.Life Sci.202128111976910.1016/j.lfs.2021.119769 34186046
     [Google Scholar]
  21. ButlerA. HelliwellM.V. ZhangY. HancoxJ.C. DempseyC.E. An update on the structure of hERG.Front. Pharmacol.202010157210.3389/fphar.2019.01572 32038248
     [Google Scholar]
  22. TsaiC.T. LaiL.P. HwangJ.J. LinJ.L. ChiangF.T. Molecular genetics of atrial fibrillation.J. Am. Coll. Cardiol.200852424125010.1016/j.jacc.2008.02.072 18634977
     [Google Scholar]
  23. AminA.S. HerfstL.J. DelisleB.P. Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome.J. Clin. Invest.200811872552256110.1172/JCI35337 18551196
     [Google Scholar]
  24. HimmelH. LagruttaA. VömelM. Nonclinical cardiovascular assessment of the soluble guanylate cyclase stimulator vericiguat.J. Pharmacol. Exp. Ther.20233861263410.1124/jpet.122.001368 37068911
     [Google Scholar]
  25. TosakiA. ArrhythmoGenoPharmacoTherapy.Front. Pharmacol.20201161610.3389/fphar.2020.00616 32477118
     [Google Scholar]
  26. HuangF.D. ChenJ. LinM. KeatingM.T. SanguinettiM.C. Long-QT syndrome-associated missense mutations in the pore helix of the HERG potassium channel.Circulation200110491071107510.1161/hc3501.093815 11524404
     [Google Scholar]
  27. ZhangY. ColensoC.K. El HarchiA. Interactions between amiodarone and the hERG potassium channel pore determined with mutagenesis and in silico docking.Biochem. Pharmacol.2016113243510.1016/j.bcp.2016.05.013 27256139
     [Google Scholar]
  28. YlliD. WartofskyL. BurmanK.D. Evaluation and treatment of amiodarone-induced thyroid disorders.J. Clin. Endocrinol. Metab.2021106122623610.1210/clinem/dgaa686 33159436
     [Google Scholar]
  29. YuY. LuoD. LiZ. Inhibitory effects of dronedarone on small conductance calcium activated potassium channels in patients with chronic atrial fibrillation: Comparison to amiodarone.Med. Sci. Monit.202026e92421510.12659/MSM.924215 32470968
     [Google Scholar]
  30. SimonenP. LommiJ. LemströmK. TolvaJ. SinisaloJ. GyllingH. Amiodarone accumulates two cholesterol precursors in myocardium: A controlled clinical study.J. Intern. Med.2023294450651410.1111/joim.13693 37400980
     [Google Scholar]
  31. MengX.D. GaoW.Q. SunZ. Amiodarone and acupuncture for cardiac arrhythmia.Medicine2019987e1454410.1097/MD.0000000000014544 30762798
     [Google Scholar]
  32. PiktelJ.S. SuenY. KoukS. Effect of amiodarone and hypothermia on arrhythmia substrates during resuscitation.J. Am. Heart Assoc.20211010e01667610.1161/JAHA.120.016676 33938226
     [Google Scholar]
  33. CaoX. ZhouM. LiuH. ChenX. LiX. JiaS. Clinical efficacy and safety of shensong yangxin capsule-amiodarone combination on heart failure complicated by ventricular arrhythmia: A meta-analysis of randomized controlled trials.Front. Pharmacol.20211261392210.3389/fphar.2021.613922 33692689
     [Google Scholar]
  34. AuerJ. BerentR. EberB. Amiodarone in the prevention and treatment of arrhythmia.Curr. Opin. Investig. Drugs20023710371044 12186264
     [Google Scholar]
  35. WaldhauserK.M. TörökM. HaH.R. Hepatocellular toxicity and pharmacological effect of amiodarone and amiodarone derivatives.J. Pharmacol. Exp. Ther.200631931413142310.1124/jpet.106.108993 16971508
     [Google Scholar]
  36. AbdullahC.S. AishwaryaR. AlamS. The molecular role of Sigmar1 in regulating mitochondrial function through mitochondrial localization in cardiomyocytes.Mitochondrion20226215917510.1016/j.mito.2021.12.002 34902622
     [Google Scholar]
  37. AishwaryaR. AbdullahC.S. MorshedM. RemexN.S. BhuiyanM.S. Sigmar1’s molecular, cellular, and biological functions in regulating cellular pathophysiology.Front. Physiol.20211270557510.3389/fphys.2021.705575 34305655
     [Google Scholar]
  38. YangH. ShenH. LiJ. GuoL.W. SIGMAR1/Sigma-1 receptor ablation impairs autophagosome clearance.Autophagy20191591539155710.1080/15548627.2019.1586248 30871407
     [Google Scholar]
  39. TagashiraH. BhuiyanM.S. ShinodaY. KawahataI. NumataT. FukunagaK. Sigma-1 receptor is involved in modification of ER-mitochondria proximity and Ca2+ homeostasis in cardiomyocytes.J. Pharmacol. Sci.2023151212813310.1016/j.jphs.2022.12.005 36707178
     [Google Scholar]
  40. YasudaS.U. SausvilleE.A. HutchinsJ.B. KennedyT. WoosleyR.L. Amiodarone-induced lymphocyte toxicity and mitochondrial function.J. Cardiovasc. Pharmacol.19962819410010.1097/00005344‑199607000‑00015 8797142
     [Google Scholar]
  41. LivakK.J. SchmittgenT.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)).Method. Methods200125440240810.1006/meth.2001.1262 11846609
     [Google Scholar]
  42. CurtisM.J. AlexanderS.P.H. CirinoG. Planning experiments: Updated guidance on experimental design and analysis and their reporting III.Br. J. Pharmacol.2022179153907391310.1111/bph.15868 35673806
     [Google Scholar]
  43. RogerV.L. Epidemiology of heart failure.Circ. Res.2013113664665910.1161/CIRCRESAHA.113.300268 23989710
     [Google Scholar]
  44. AmesM.K. AtkinsC.E. PittB. The renin‐angiotensin‐aldosterone system and its suppression.J. Vet. Intern. Med.201933236338210.1111/jvim.15454 30806496
     [Google Scholar]
  45. SchwaiblmairM. BerghausT. HaeckelT. WagnerT. von ScheidtW. Amiodarone-induced pulmonary toxicity: An under-recognized and severe adverse effect?Clin. Res. Cardiol.2010991169370010.1007/s00392‑010‑0181‑3 20623129
     [Google Scholar]
  46. ColbyR. GeyerH. Amiodarone-induced pulmonary toxicity.JAAPA20173011232610.1097/01.JAA.0000524713.17719.c8 29064934
     [Google Scholar]
  47. KengL.T. LiaoM.T. Amiodarone-induced hepatic and pulmonary toxicity.Postgrad. Med. J.201894111660310.1136/postgradmedj‑2018‑135779 29743186
     [Google Scholar]
  48. LiaoR. YanF. ZengZ. Amiodarone-induced retinal neuronal cell apoptosis attenuated by IGF-1 via counter regulation of the PI3k/Akt/FoxO3a pathway.Mol. Neurobiol.20175496931694310.1007/s12035‑016‑0211‑x 27774572
     [Google Scholar]
  49. ChoiI.S. KimB.S. ChoK.S. Amiodarone induces apoptosis in L-132 human lung epithelial cell line.Toxicol. Lett.20021321475510.1016/S0378‑4274(02)00065‑6 12084619
     [Google Scholar]
  50. LiaoR. YanF. ZengZ. Insulin‐like growth factor‐1 activates PI3K/Akt signalling to protect human retinal pigment epithelial cells from amiodarone‐induced oxidative injury.Br. J. Pharmacol.2018175112513910.1111/bph.14078 29057462
     [Google Scholar]
  51. KarkhanisA. LeowJ.W.H. HagenT. ChanE.C.Y. Dronedarone-induced cardiac mitochondrial dysfunction and its mitigation by epoxyeicosatrienoic acids.Toxicol. Sci.20181631799110.1093/toxsci/kfy011
     [Google Scholar]
  52. VarbiroG. TothA. TapodiA. VeresB. SumegiB. GallyasF.Jr Concentration dependent mitochondrial effect of amiodarone.Biochem. Pharmacol.20036571115112810.1016/S0006‑2952(02)01660‑X 12663047
     [Google Scholar]
  53. ZahnoA. BrechtK. MorandR. The role of CYP3A4 in amiodarone-associated toxicity on HepG2 cells.Biochem. Pharmacol.201181343244110.1016/j.bcp.2010.11.002 21070748
     [Google Scholar]
  54. ZweierJ.L. FlahertyJ.T. WeisfeldtM.L. Direct measurement of free radical generation following reperfusion of ischemic myocardium.Proc. Natl. Acad. Sci.19878451404140710.1073/pnas.84.5.1404 3029779
     [Google Scholar]
  55. GarlickP.B. DaviesM.J. HearseD.J. SlaterT.F. Direct detection of free radicals in the reperfused rat heart using electron spin resonance spectroscopy.Circ. Res.198761575776010.1161/01.RES.61.5.757 2822281
     [Google Scholar]
  56. KomarovD.A. SamouilovA. HirataH. ZweierJ.L. High fidelity triangular sweep of the magnetic field for millisecond scan EPR imaging.J. Magn. Reson.202132910702410.1016/j.jmr.2021.107024 34198184
     [Google Scholar]
  57. PietriS. CulcasiM. StellaL. CozzoneP.J. Ascorbyl free radical as a reliable indicator of free‐radical‐mediated myocardial ischemic and post‐ischemic injury.Eur. J. Biochem.1990193384585410.1111/j.1432‑1033.1990.tb19408.x 2174367
     [Google Scholar]
  58. BlasigI.E. EbertB. HennigC. PaliT. TosakiA. Inverse relationship between ESR spin trapping of oxyradicals and degree of functional recovery during myocardial reperfusion in isolated working rat heart.Cardiovasc. Res.199024426327010.1093/cvr/24.4.263 2161288
     [Google Scholar]
  59. TosakiA. BraquetP. DMPO and reperfusion injury: Arrhythmia, heart function, electron spin resonance, and nuclear magnetic resonance studies in isolated working guinea pig hearts.Am. Heart J.1990120481983010.1016/0002‑8703(90)90197‑6 2171311
     [Google Scholar]
  60. KadenbachB. RamzanR. MoosdorfR. VogtS. The role of mitochondrial membrane potential in ischemic heart failure.Mitochondrion201111570070610.1016/j.mito.2011.06.001 21703366
     [Google Scholar]
  61. HoutenS.M. ViolanteS. VenturaF.V. WandersR.J.A. The biochemistry and physiology of mitochondrial fatty acid β-oxidation and its genetic disorders.Annu. Rev. Physiol.2016781234410.1146/annurev‑physiol‑021115‑105045 26474213
     [Google Scholar]
  62. WelchenE. GonzalezD.H. Cytochrome c, a hub linking energy, redox, stress and signaling pathways in mitochondria and other cell compartments.Physiol. Plant.2016157331032110.1111/ppl.12449 27080474
     [Google Scholar]
  63. KimT.Y. TerentyevaR. RoderK.H. SK channel enhancers attenuate Ca2+-dependent arrhythmia in hypertrophic hearts by regulating mito-ROS-dependent oxidation and activity of RyR.Cardiovasc. Res.20171133343353 28096168
     [Google Scholar]
  64. KitajimaN. Numaga-TomitaT. WatanabeM. TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling.Sci. Rep.2016613700110.1038/srep37001 27833156
     [Google Scholar]
  65. XuanY. LiuS. LiY. Short-term vagus nerve stimulation reduces myocardial apoptosis by downregulating microRNA-205 in rats with chronic heart failure.Mol. Med. Rep.20171655847585410.3892/mmr.2017.7344 28849082
     [Google Scholar]
  66. YinW. LiR. FengX. JamesK.Y. The involvement of cytochrome c oxidase in mitochondrial fusion in primary cultures of neonatal rat cardiomyocytes.Cardiovasc. Toxicol.201818436537310.1007/s12012‑018‑9447‑1 29396798
     [Google Scholar]
  67. RobichauxD.J. HarataM. MurphyE. KarchJ. Mitochondrial permeability transition pore-dependent necrosis.J. Mol. Cell. Cardiol.2023174475510.1016/j.yjmcc.2022.11.003 36410526
     [Google Scholar]
  68. JainA. StackO. GhodratiS. KCNH2 encodes a nuclear-targeted polypeptide that mediates hERG1 channel gating and expression.Proc. Natl. Acad. Sci.20231203e221470012010.1073/pnas.2214700120 36626562
     [Google Scholar]
  69. AbdullahC.S. AlamS. AishwaryaR. Cardiac dysfunction in the sigma 1 receptor knockout mouse associated with impaired mitochondrial dynamics and bioenergetics.J. Am. Heart Assoc.2018720e00977510.1161/JAHA.118.009775 30371279
     [Google Scholar]
  70. SugiyamaH. NakamuraK. MoritaH. Circulating KCNH2 current-activating factor in patients with heart failure and ventricular tachyarrhythmia.PLoS One201165e1989710.1371/journal.pone.0019897 21625547
     [Google Scholar]
  71. GongQ. StumpM.R. ZhouZ. Regulation of Kv11.1 potassium channel C-terminal isoform expression by the RNA-binding proteins HuR and HuD.J. Biol. Chem.201829351196241963210.1074/jbc.RA118.003720 30377250
     [Google Scholar]
  72. van den BoogaardM. van WeerdJ.H. BawazeerA.C. Identification and characterization of a transcribed distal enhancer involved in cardiac kcnh2 regulation.Cell Rep.2019281027042714.e510.1016/j.celrep.2019.08.007 31484079
     [Google Scholar]
  73. GuoF. SunY. WangX. Patient-specific and gene-corrected induced pluripotent stem cell-derived cardiomyocytes elucidate single-cell phenotype of short QT syndrome.Circ. Res.20191241667810.1161/CIRCRESAHA.118.313518 30582453
     [Google Scholar]
  74. McDevittJ. RubinL.H. De SimoneF.I. PhillipsJ. LangfordD. Association between (GT)n promoter polymorphism and recovery from concussion: A pilot study.J. Neurotrauma202037101204121010.1089/neu.2019.6590 31847698
     [Google Scholar]
  75. NakamuraK. KatayamaY. KusanoK.F. Anti-KCNH2 antibody-induced long QT syndrome: Novel acquired form of long QT syndrome.J. Am. Coll. Cardiol.200750181808180910.1016/j.jacc.2007.07.037 17964047
     [Google Scholar]
  76. MoonC.H. KimM.Y. KimM.J. KR-31378, a novel benzopyran analog, attenuates hypoxia-induced cell death via mitochondrial KATP channel and protein kinase C-ɛ in heart-derived H9c2 cells.Eur. J. Pharmacol.20045061273510.1016/j.ejphar.2004.10.037 15588621
     [Google Scholar]
  77. StaudacherI. WangL. WanX. hERG K+ channel-associated cardiac effects of the antidepressant drug desipramine.Naunyn Schmiedebergs Arch. Pharmacol.2011383211913910.1007/s00210‑010‑0583‑9 21120454
     [Google Scholar]
/content/journals/cmm/10.2174/0115665240265771231129105108
Loading
Amiodarone Advances the Apoptosis of Cardiomyocytes by Repressing Sigmar1 Expression and Blocking KCNH2-related Potassium Channels
Current Molecular Medicine 25, 69 (2025); https://doi.org/10.2174/0115665240265771231129105108
/content/journals/cmm/10.2174/0115665240265771231129105108
/content/journals/cmm/10.2174/0115665240265771231129105108
Loading

Data & Media loading...


  • Article Type:     Research Article
Keyword(s): Amiodarone; H9c2 cells; heart failure; potassium; Sigmar1; subfamily H member 2; voltage-gated cannel

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test