Cardiotoxicity of chloroquine and hydroxychloroquine through mitochondrial pathway.
Cardiotoxicity
Chloroquine
Hydroxychloroquine
Mitochondria
Oxidative stress
Journal
BMC pharmacology & toxicology
ISSN: 2050-6511
Titre abrégé: BMC Pharmacol Toxicol
Pays: England
ID NLM: 101590449
Informations de publication
Date de publication:
21 04 2023
21 04 2023
Historique:
received:
07
01
2023
accepted:
27
03
2023
medline:
25
4
2023
pubmed:
22
4
2023
entrez:
21
04
2023
Statut:
epublish
Résumé
Medical therapies can cause cardiotoxicity. Chloroquine (QC) and hydroxychloroquine (HQC) are drugs used in the treatment of malaria and skin and rheumatic disorders. These drugs were considered to help treatment of coronavirus disease (COVID-19) in 2019. Despite the low cost and availability of QC and HQC, reports indicate that this class of drugs can cause cardiotoxicity. The mechanism of this event is not well known, but evidence shows that QC and HQC can cause cardiotoxicity by affecting mitochondria and lysosomes. Therefore, our study was designed to investigate the effects of QC and HQC on heart mitochondria. In order to achieve this aim, mitochondrial function, reactive oxygen species (ROS) level, mitochondrial membrane disruption, and cytochrome c release in heart mitochondria were evaluated. Statistical significance was determined using the one-way and two-way analysis of variance (ANOVA) followed by post hoc Tukey to evaluate mitochondrial succinate dehydrogenase (SDH) activity and cytochrome c release, and Bonferroni test to evaluate the ROS level, mitochondrial membrane potential (MMP) collapse, and mitochondrial swelling. Based on ANOVA analysis (one-way), the results of mitochondrial SDH activity showed that the IC The results suggest that QC and HQC can cause cardiotoxicity which can lead to heart disorders through oxidative stress and disfunction of heart mitochondria.
Sections du résumé
BACKGROUND
Medical therapies can cause cardiotoxicity. Chloroquine (QC) and hydroxychloroquine (HQC) are drugs used in the treatment of malaria and skin and rheumatic disorders. These drugs were considered to help treatment of coronavirus disease (COVID-19) in 2019. Despite the low cost and availability of QC and HQC, reports indicate that this class of drugs can cause cardiotoxicity. The mechanism of this event is not well known, but evidence shows that QC and HQC can cause cardiotoxicity by affecting mitochondria and lysosomes.
METHODS
Therefore, our study was designed to investigate the effects of QC and HQC on heart mitochondria. In order to achieve this aim, mitochondrial function, reactive oxygen species (ROS) level, mitochondrial membrane disruption, and cytochrome c release in heart mitochondria were evaluated. Statistical significance was determined using the one-way and two-way analysis of variance (ANOVA) followed by post hoc Tukey to evaluate mitochondrial succinate dehydrogenase (SDH) activity and cytochrome c release, and Bonferroni test to evaluate the ROS level, mitochondrial membrane potential (MMP) collapse, and mitochondrial swelling.
RESULTS
Based on ANOVA analysis (one-way), the results of mitochondrial SDH activity showed that the IC
CONCLUSIONS
The results suggest that QC and HQC can cause cardiotoxicity which can lead to heart disorders through oxidative stress and disfunction of heart mitochondria.
Identifiants
pubmed: 37085872
doi: 10.1186/s40360-023-00666-x
pii: 10.1186/s40360-023-00666-x
pmc: PMC10119838
doi:
Substances chimiques
Hydroxychloroquine
4QWG6N8QKH
Chloroquine
886U3H6UFF
Reactive Oxygen Species
0
Cytochromes c
9007-43-6
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
26Informations de copyright
© 2023. The Author(s).
Références
Chatre C, Roubille F, Vernhet H, Jorgensen C, Pers YM. Cardiac Complications Attributed to Chloroquine and Hydroxychloroquine: A Systematic Review of the Literature. Drug Saf 2018;41(10):919 – 31. ^10.1007/s40264-018-0689-4.
Goldman A, Bomze D, Dankner R, Hod H, Meirson T, Boursi B et al. Cardiovascular adverse events associated with hydroxychloroquine and chloroquine: A comprehensive pharmacovigilance analysis of pre-COVID-19 reports. Br J Clin Pharmacol 2021;87(3):1432-42. ^10.1111/bcp.14546.
Mubagwa K. Cardiac effects and toxicity of chloroquine: a short update. Int J Antimicrob Agents 2020;56(2):106057. ^10.1016/j.ijantimicag.2020.106057.
Jankelson L, Karam G, Becker ML, Chinitz LA, Tsai MC. QT prolongation, torsades de pointes, and sudden death with short courses of chloroquine or hydroxychloroquine as used in COVID-19: A systematic review. Heart Rhythm 2020;17(9):1472-9. ^ https://doi.org/10.1016/j.hrthm.2020.05.008 .
Klouda CB, Stone WL. Oxidative Stress, Proton Fluxes, and Chloroquine/Hydroxychloroquine Treatment for COVID-19. Antioxidants (Basel) 2020;9(9). ^10.3390/antiox9090894.
Vessoni AT, Quinet A, de Andrade-Lima LC, Martins DJ, Garcia CC, Rocha CR et al. Chloroquine-induced glioma cells death is associated with mitochondrial membrane potential loss, but not oxidative stress. Free Radic Biol Med 2016;90:91–100. ^10.1016/j.freeradbiomed.2015.11.008.
Sorour AA, Kurmann RD, Shahin YE, Crowson CS, Achenbach SJ, Mankad R et al. Use of Hydroxychloroquine and Risk of Heart Failure in Patients With Rheumatoid Arthritis. J Rheumatol 2021;48(10):1508-11. ^10.3899/jrheum.201180.
Yogasundaram H, Hung W, Paterson ID, Sergi C, Oudit GY. Chloroquine-induced cardiomyopathy: a reversible cause of heart failure. ESC Heart Fail 2018;5(3):372-5. ^10.1002/ehf2.12276.
Nadeem U, Raafey M, Kim G, Treger J, Pytel P et al. A NH,. Chloroquine- and Hydroxychloroquine-Induced Cardiomyopathy: A Case Report and Brief Literature Review. Am J Clin Pathol 2021;155(6):793–801. ^10.1093/ajcp/aqaa253.
Liang DH, Choi DS, Ensor JE, Kaipparettu BA, Bass BL, Chang JC. The autophagy inhibitor chloroquine targets cancer stem cells in triple negative breast cancer by inducing mitochondrial damage and impairing DNA break repair. Cancer Lett 2016;376(2):249 – 58. ^10.1016/j.canlet.2016.04.002.
Liu L, Han C, Yu H, Zhu W, Cui H, Zheng L et al. Chloroquine inhibits cell growth in human A549 lung cancer cells by blocking autophagy and inducing mitochondrial–mediated apoptosis. Oncol Rep 2018;39(6):2807–16. ^10.3892/or.2018.6363.
Qu X, Sheng J, Shen L, Su J, Xu Y, Xie Q et al. Autophagy inhibitor chloroquine increases sensitivity to cisplatin in QBC939 cholangiocarcinoma cells by mitochondrial ROS. PLoS One 2017;12(3):e0173712. ^10.1371/journal.pone.0173712.
Christen F, Desrosiers V, Dupont-Cyr BA, Vandenberg GW, Le François NR, Tardif JC et al. Thermal tolerance and thermal sensitivity of heart mitochondria: Mitochondrial integrity and ROS production. Free Radic Biol Med 2018;116:11 – 8. ^10.1016/j.freeradbiomed.2017.12.037.
Odinokova I, Baburina Y, Kruglov A, Fadeeva I, Zvyagina A, Sotnikova L et al. Effect of Melatonin on Rat Heart Mitochondria in Acute Heart Failure in Aged Rats. Int J Mol Sci 2018;19(6). ^10.3390/ijms19061555.
Sabbah HN. Targeting the Mitochondria in Heart Failure: A Translational Perspective. JACC Basic Transl Sci 2020;5(1):88–106. ^10.1016/j.jacbts.2019.07.009.
Cao T, Fan S, Zheng D, Wang G, Yu Y, Chen R et al. Increased calpain-1 in mitochondria induces dilated heart failure in mice: role of mitochondrial superoxide anion. Basic Res Cardiol 2019;114(3):17. ^10.1007/s00395-019-0726-1.
Peoples JN, Saraf A, Ghazal N, Pham TT, Kwong JQ. Mitochondrial dysfunction and oxidative stress in heart disease. Exp Mol Med 2019;51(12):1–13. ^10.1038/s12276-019-0355-7.
Zhang H, Liu B, Li T, Zhu Y, Luo G, Jiang Y et al. AMPK activation serves a critical role in mitochondria quality control via modulating mitophagy in the heart under chronic hypoxia. Int J Mol Med 2018;41(1):69–76. ^10.3892/ijmm.2017.3213.
Kelso EJ, McDermott BJ, Silke B. Actions of the novel vasodilator, flosequinan, in isolated ventricular cardiomyocytes. J Cardiovasc Pharmacol. 1995;25(3):376–86.
doi: 10.1097/00005344-199503000-00005
pubmed: 7769801
Salimi A, Roudkenar MH, Sadeghi L, Mohseni A, Seydi E, Pirahmadi N, Pourahmad J. Selective Anticancer Activity of Acacetin Against Chronic Lymphocytic Leukemia Using Both In Vivo and In Vitro Methods: Key Role of Oxidative Stress and Cancerous Mitochondria. Nutr Cancer. 2016;68(8):1404–1416. ^ https://doi.org/10.1080/01635581.2016.1235717 .
doi: 10.1080/15569543.2019.1700382
Westfall MV, Rust EM, Albayya F, Metzger JM. Adenovirus—mediated myofilament gene transfer into adult Cardiac Myocytes. Methods Cell Biol. 1997;52:307–22.
doi: 10.1016/S0091-679X(08)60385-4
pubmed: 9379958
Zhao Y, Ye L, Liu H, Xia Q, Zhang Y, Yang X et al. Vanadium compounds induced mitochondria permeability transition pore (PTP) opening related to oxidative stress. J Inorg Biochem 2010;104(4):371–8. ^ https://doi.org/10.1016/j.jinorgbio.2009.11.007 .
Pourahmad J, Eskandari MR, Nosrati M, Kobarfard F, Khajeamiri AR. Involvement of mitochondrial/lysosomal toxic cross-talk in ecstasy induced liver toxicity under hyperthermic condition. Eur J Pharmacol. 2010;643(2-3):162–9. ^ https://doi.org/10.1016/j.ejphar.2010.06.019 .
doi: 10.1016/S0005-2728(03)00110-5
pubmed: 14507434
Junior RFR, Dabkowski ER, Shekar KC, Hecker PA, Murphy MP. MitoQ improves mitochondrial dysfunction in heart failure induced by pressure overload. Free Radic Biol Med. 2018;117:18–29.
doi: 10.1016/j.freeradbiomed.2018.01.012
Sheaff RJ. A New Model of SARS-CoV-2 Infection Based on (Hydroxy) Chloroquine Activity. bioRxiv 2020:2020.08. 02.232892.
Khosa S, Khanlou N, Khosa GS, Mishra SK. Hydroxychloroquine-induced autophagic vacuolar myopathy with mitochondrial abnormalities. Neuropathology. 2018;38(6):646–52.
doi: 10.1111/neup.12520
pubmed: 30411412
Boengler K, Kosiol M, Mayr M, Schulz R, Rohrbach S. Mitochondria and ageing: role in heart, skeletal muscle and adipose tissue. J cachexia sarcopenia muscle. 2017;8(3):349–69.
doi: 10.1002/jcsm.12178
pubmed: 28432755
pmcid: 5476857
Bou-Teen D, Kaludercic N, Weissman D, Turan B, Maack C, Di Lisa F, et al. Mitochondrial ROS and mitochondria-targeted antioxidants in the aged heart. Free Radic Biol Med. 2021;167:109–24.
doi: 10.1016/j.freeradbiomed.2021.02.043
pubmed: 33716106
Martín-Fernández B, Gredilla R. Mitochondria and oxidative stress in heart aging. Age. 2016;38(4):225–38.
doi: 10.1007/s11357-016-9933-y
pubmed: 27449187
pmcid: 5061683
Abou-El-Hassan MA, Rabelink MJ, van der Vijgh WJ, Bast A, Hoeben RC. A comparative study between catalase gene therapy and the cardioprotector monohydroxyethylrutoside (MonoHER) in protecting against doxorubicin-induced cardiotoxicity in vitro. Br J Cancer 2003;89(11):2140-6. ^10.1038/sj.bjc.6601430.
Khalil SR, Mohammed WA, Zaglool AW, Elhady WM, Farag MR, El Sayed SAM. Inflammatory and oxidative injury is induced in cardiac and pulmonary tissue following fipronil exposure in Japanese quail: mRNA expression of the genes encoding interleukin 6, nuclear factor kappa B, and tumor necrosis factor-alpha. Environ Pollut 2019;251:564 – 72. ^10.1016/j.envpol.2019.05.012.
Chaanine AH, Gordon RE, Nonnenmacher M, Kohlbrenner E, Benard L, Hajjar RJ. High-dose chloroquine is metabolically cardiotoxic by inducing lysosomes and mitochondria dysfunction in a rat model of pressure overload hypertrophy. Physiological Rep. 2015;3(7):e12413.
doi: 10.14814/phy2.12413
Pena E, El Alam S, Siques P, Brito J. Oxidative stress and diseases associated with high-altitude exposure. Antioxidants. 2022;11(2):267.
doi: 10.3390/antiox11020267
pubmed: 35204150
pmcid: 8868315
Remigante A, Morabito R. Cellular and molecular mechanisms in oxidative stress-related diseases. MDPI; 2022. p. 8017.
Bansal Y, Kuhad A. Mitochondrial dysfunction in depression. Curr Neuropharmacol. 2016;14(6):610–8.
doi: 10.2174/1570159X14666160229114755
pubmed: 26923778
pmcid: 4981740
de Mello AH, Costa AB, Engel JDG, Rezin GT. Mitochondrial dysfunction in obesity. Life Sci. 2018;192:26–32.
doi: 10.1016/j.lfs.2017.11.019
pubmed: 29155300
Kumar V, Santhosh Kumar T, Kartha C. Mitochondrial membrane transporters and metabolic switch in heart failure. Heart Fail Rev. 2019;24(2):255–67.
doi: 10.1007/s10741-018-9756-2
pubmed: 30535838
Zorova LD, Popkov VA, Plotnikov EY, Silachev DN, Pevzner IB, Jankauskas SS, et al. Mitochondrial membrane potential. Anal Biochem. 2018;552:50–9.
doi: 10.1016/j.ab.2017.07.009
Crowley LC, Christensen ME, Waterhouse NJ. Measuring mitochondrial transmembrane potential by TMRE staining. Cold Spring Harbor Protocols 2016;2016(12):pdb. prot087361.
Zhang M, Zheng J, Nussinov R, Ma B. Release of cytochrome C from bax pores at the mitochondrial membrane. Sci Rep. 2017;7(1):1–13.
Chistiakov DA, Shkurat TP, Melnichenko AA, Grechko AV, Orekhov AN. The role of mitochondrial dysfunction in cardiovascular disease: a brief review. Ann Med. 2018;50(2):121–7.
doi: 10.1080/07853890.2017.1417631
pubmed: 29237304
Zhou B, Tian R. Mitochondrial dysfunction in pathophysiology of heart failure. J Clin Investig. 2018;128(9):3716–26.
doi: 10.1172/JCI120849
pubmed: 30124471
pmcid: 6118589