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2000
Volume 25, Issue 7
  • ISSN: 1568-0096
  • E-ISSN: 1873-5576

Abstract

Introduction

The cardiotoxicity and subsequent Heart Failure (HF) induced by Doxorubicin (DOX) limit the clinical application of DOX. Valsartan (Val) is an angiotensin II receptor blocker that could attenuate the HF induced by DOX. However, the underlying mechanism of Val in this process is not fully understood.

Methods

In this study, we explored the cardio-protective mechanism of Val against DOX-induced cardiotoxicity using label-free ubiquitin-proteomic analysis.

Results

Results showed that 27 lysine-ubiquitination sites in 25 proteins were differentially expressed between DOX and DOX+Val treated groups. In addition, the levels of ubiquitin modification of the myosin family and Ankrd1 were upregulated post-Val. Val also increased ATP production and activated the Akt/mTOR pathway by regulating the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a) and cardiomyocyte calcium hemostasis.

Conclusion

The results highlight the value of label-free ubiquitin-proteomic analysis in defining the molecular mechanism of Val against HF and may be helpful in the development of new therapeutic agents for HF targeting molecules defined in this research.

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References

  1. MonteranL. ErshaidN. DoronH. Chemotherapy-induced complement signaling modulates immunosuppression and metastatic relapse in breast cancer.Nat. Commun.2022131579710.1038/s41467‑022‑33598‑x 36184683
     [Google Scholar]
  2. RutherfordS.C. AbramsonJ.S. BartlettN.L. Venetoclax with dose-adjusted EPOCH-R as initial therapy for patients with aggressive B-cell lymphoma: A single-arm, multicentre, phase 1 study.Lancet Haematol.2021811e818e82710.1016/S2352‑3026(21)00273‑8 34634256
     [Google Scholar]
  3. GorodnovaT.V. SokolenkoA.P. KuliginaE. BerlevI.V. ImyanitovE.N. Principles of clinical management of ovarian cancer.Chin Clin Oncol20187656 30509078
     [Google Scholar]
  4. HongY. CheS. HuiB. Lung cancer therapy using doxorubicin and curcumin combination: Targeted prodrug based, pH sensitive nanomedicine.Biomed. Pharmacother.201911210861410.1016/j.biopha.2019.108614 30798129
     [Google Scholar]
  5. SawickiK.T. SalaV. PreverL. HirschE. ArdehaliH. Preventing and treating Anthracycline Cardiotoxicity: New insights.Annu. Rev. Pharmacol. Toxicol.2021611309332
     [Google Scholar]
  6. ArmenianS. BhatiaS. Predicting and preventing Anthracycline-related cardiotoxicity.Am. Soc. Clin. Oncol. Educ. Book2018383831210.1200/EDBK_100015 30231396
     [Google Scholar]
  7. ZhaoY. LiQ. NiuJ. Neutrophil membrane-camouflaged polyprodrug nanomedicine for inflammation suppression in ischemic stroke therapy.Adv. Mater.20243621e231180310.1002/adma.202311803 38519052
     [Google Scholar]
  8. HuoM. TangZ. WangL. Magnesium hexacyanoferrate nanocatalysts attenuate chemodrug-induced cardiotoxicity through an anti-apoptosis mechanism driven by modulation of ferrous iron.Nat. Commun.2022131777810.1038/s41467‑022‑35503‑y 36522337
     [Google Scholar]
  9. DochertyK.F. VaduganathanM. SolomonS.D. McMurrayJ.J.V. Sacubitril/Valsartan: Neprilysin inhibition 5 years after PARADIGM-HF.JACC Heart Fail.202081080081010.1016/j.jchf.2020.06.020 33004114
     [Google Scholar]
  10. VaderJ.M. GivertzM.M. StarlingR.C. Tolerability of Sacubitril/Valsartan in patients with advanced heart failure: Analysis of the life trial run-in.JACC Heart Fail.202210744945610.1016/j.jchf.2022.04.013 35772853
     [Google Scholar]
  11. BoutagyN.E. FeherA. PfauD. Dual angiotensin receptor-neprilysin inhibition with Sacubitril/Valsartan attenuates systolic dysfunction in experimental doxorubicin-induced cardiotoxicity.JACC: CardioOncol202025774787 33437965
     [Google Scholar]
  12. KimB.S. ParkI.H. LeeA.H. KimH.J. LimY.H. ShinJ-H. Sacubitril/valsartan reduces endoplasmic reticulum stress in a rat model of doxorubicin-induced cardiotoxicity.Arch. Toxicol.20229641065107410.1007/s00204‑022‑03241‑1 35152301
     [Google Scholar]
  13. ChengD. TuW. ChenL. MSCs enhances the protective effects of valsartan on attenuating the doxorubicin-induced myocardial injury via AngII/NOX/ROS/MAPK signaling pathway.Aging (Albany NY)20211318225562257010.18632/aging.203569 34587120
     [Google Scholar]
  14. FinanC. GaultonA. KrugerF.A. The druggable genome and support for target identification and validation in drug development.Sci. Transl. Med.20179383eaag116610.1126/scitranslmed.aag1166 28356508
     [Google Scholar]
  15. HenryA. Gordillo-MarañónM. FinanC. Therapeutic targets for heart failure identified using proteomics and mendelian randomization.Circulation2022145161205121710.1161/CIRCULATIONAHA.121.056663 35300523
     [Google Scholar]
  16. ShenY. ZhangH. NiY. Tripartite motif 25 ameliorates doxorubicin-induced cardiotoxicity by degrading p85α.Cell Death Dis.202213764310.1038/s41419‑022‑05100‑4 35871160
     [Google Scholar]
  17. EckertM.A. CosciaF. ChryplewiczA. Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts.Nature2019569775872372810.1038/s41586‑019‑1173‑8 31043742
     [Google Scholar]
  18. KalxdorfM. MüllerT. StegleO. KrijgsveldJ. IceR improves proteome coverage and data completeness in global and single-cell proteomics.Nat. Commun.2021121478710.1038/s41467‑021‑25077‑6 34373457
     [Google Scholar]
  19. FriedrichC. SchallenbergS. KirchnerM. Comprehensive micro-scaled proteome and phosphoproteome characterization of archived retrospective cancer repositories.Nat. Commun.2021121357610.1038/s41467‑021‑23855‑w 34117251
     [Google Scholar]
  20. ScheffnerM. NuberU. HuibregtseJ.M. Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin thioester cascade.Nature19953736509818310.1038/373081a0 7800044
     [Google Scholar]
  21. SongL. LuoZ.Q. Post-translational regulation of ubiquitin signaling.J. Cell Biol.201921861776178610.1083/jcb.201902074 31000580
     [Google Scholar]
  22. ZhaoS. HuangC. YangY. DNA repair protein FANCD2 has both ubiquitination-dependent and ubiquitination-independent functions during germ cell development.J. Biol. Chem.2023299310290510.1016/j.jbc.2023.102905 36642183
     [Google Scholar]
  23. NakazawaY. HaraY. OkaY. Ubiquitination of DNA damage-stalled RNAPII promotes transcription-coupled repair.Cell2020180612281244.e2410.1016/j.cell.2020.02.010 32142649
     [Google Scholar]
  24. XiaoW. HeZ. LuoW. BYHWD alleviates inflammatory response by NIK-mediated repression of the noncanonical NF-κB pathway during ICH recovery.Front. Pharmacol.20211263240710.3389/fphar.2021.632407 34025405
     [Google Scholar]
  25. DayS.M. The ubiquitin proteasome system in human cardiomyopathies and heart failure.Am. J. Physiol. Heart Circ. Physiol.201330410H1283H129310.1152/ajpheart.00249.2012 23479263
     [Google Scholar]
  26. PaganJ. SetoT. PaganoM. CittadiniA. Role of the ubiquitin proteasome system in the heart.Circ. Res.201311271046105810.1161/CIRCRESAHA.112.300521 23538275
     [Google Scholar]
  27. WuP. LiY. CaiM. Ubiquitin carboxyl-terminal hydrolase L1 of Cardiomyocytes promotes macroautophagy and proteostasis and protects against post-myocardial infarction cardiac remodeling and heart failure.Front. Cardiovasc. Med.2022986690110.3389/fcvm.2022.866901 35463782
     [Google Scholar]
  28. HansenF.M. TanzerM.C. BrüningF. Data-independent acquisition method for ubiquitinome analysis reveals regulation of circadian biology.Nat. Commun.202112125410.1038/s41467‑020‑20509‑1 33431886
     [Google Scholar]
  29. EapenV.V. SwarupS. HoyerM.J. PauloJ.A. HarperJ.W. Quantitative proteomics reveals the selectivity of ubiquitin-binding autophagy receptors in the turnover of damaged lysosomes by lysophagy.eLife202110e7232810.7554/eLife.72328 34585663
     [Google Scholar]
  30. MiyoshiT. NakamuraK. AmiokaN. LCZ696 ameliorates doxorubicin-induced cardiomyocyte toxicity in rats.Sci. Rep.2022121493010.1038/s41598‑022‑09094‑z 35322164
     [Google Scholar]
  31. PeoplesJ.N. SarafA. GhazalN. PhamT.T. KwongJ.Q. Mitochondrial dysfunction and oxidative stress in heart disease.Exp. Mol. Med.2019511211310.1038/s12276‑019‑0355‑7 31857574
     [Google Scholar]
  32. ZuoY. XiangB. YangJ. Oxidative modification of caspase-9 facilitates its activation via disulfide-mediated interaction with Apaf-1.Cell Res.200919444945710.1038/cr.2009.19 19238172
     [Google Scholar]
  33. ChenM. GuerreroA.D. HuangL. Caspase-9-induced mitochondrial disruption through cleavage of anti-apoptotic BCL-2 family members.J. Biol. Chem.200728246338883389510.1074/jbc.M702969200 17893147
     [Google Scholar]
  34. JiangY. SuS. ZhangY. QianJ. LiuP. Control of mTOR signaling by ubiquitin.Oncogene201938213989400110.1038/s41388‑019‑0713‑x 30705402
     [Google Scholar]
  35. LuP. WuB. FengX. ChengW. KitsisR.N. Cardiac myosin heavy chain reporter mice to study heart development and disease.Circ. Res.2022131436436610.1161/CIRCRESAHA.122.321461 35862119
     [Google Scholar]
  36. LingS.S.M. ChenY.T. WangJ. RichardsA.M. LiewO.W. Ankyrin repeat domain 1 protein: A functionally pleiotropic protein with cardiac biomarker potential.Int. J. Mol. Sci.2017187136210.3390/ijms18071362 28672880
     [Google Scholar]
  37. PiroddiN. PesceP. ScelliniB. Myocardial overexpression of ANKRD1 causes sinus venosus defects and progressive diastolic dysfunction.Cardiovasc. Res.202011681458147210.1093/cvr/cvz291 31688894
     [Google Scholar]
  38. SantulliG. XieW. ReikenS.R. MarksA.R. Mitochondrial calcium overload is a key determinant in heart failure.Proc. Natl. Acad. Sci. USA201511236113891139410.1073/pnas.1513047112 26217001
     [Google Scholar]
  39. KawaseY. HajjarR.J. The cardiac sarcoplasmic/endoplasmic reticulum calcium ATPase: A potent target for cardiovascular diseases.Nat. Clin. Pract. Cardiovasc. Med.20085955456510.1038/ncpcardio1301 18665137
     [Google Scholar]
  40. Bachar-WikstromE. CurmanP. AhanianT. Darier disease is associated with heart failure: A cross-sectional case-control and population based study.Sci. Rep.2020101688610.1038/s41598‑020‑63832‑9 32327688
     [Google Scholar]
  41. HanJ. FangZ. HanB. Deubiquitinase JOSD2 improves calcium handling and attenuates cardiac hypertrophy and dysfunction by stabilizing SERCA2a in cardiomyocytes.Nat Cardiovasc Res20232876477710.1038/s44161‑023‑00313‑y 39195964
     [Google Scholar]
  42. AbeyrathnaP. SuY. The critical role of Akt in cardiovascular function.Vascul. Pharmacol.201574384810.1016/j.vph.2015.05.008 26025205
     [Google Scholar]
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Value of Label-Free Ubiquitin-Proteomic Analysis on Defining the Protective Mechanism of Valsartan against Doxorubicin-Induced Heart Failure
Curr. Cancer Drug Targets< 25, 795 (2025); https://doi.org/10.2174/0115680096341637241231111922
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  • Article Type:     Research Article
Keyword(s): Akt/mTOR pathway; cardiotoxicity; Doxorubicin; heart failure; ubiquitin-proteomics; valsartan

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