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Selenium Supplementation Protects Against Arsenic-Trioxide-Induced Cardiotoxicity Via Reducing Oxidative Stress and Inflammation Through Increasing NAD+ Pool

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Abstract

Arsenic is an environmental contaminant, and accumulating evidence has indicated that exposure to arsenic can cause various diseases, especially cardiotoxicity. Selenium (Se) exerts a vital role in the regulation of multiple physiological activities. Recently, several studies highlighted that Se treatment can effectively antagonize the toxic effects induced by arsenic. However, the exact underlying effect and mechanism of Se on Arsenic-induced cardiotoxicity has not been explored. In the current study, the arsenic trioxide (ATO)-triggered heart damage mice model was used to explore whether Se exerts protective roles in ATO-related cardiotoxicity and its potential mechanism. Our data showed that Se treatment significantly alleviated ATO-mediated cardiotoxicity evidenced by increased weight, decreased myocardial damage markers, and improved heart functions in mice. Furthermore, we demonstrated that Se remarkably inhibited ATO-mediated oxidative stress and inflammatory responses in heart tissues. Mechanistically, we showed that Se upregulated the levels of NAD+ in cardiomyocytes of the mice challenged by ATO, and this effect involved in the activation of the NAD+ biosynthesis through the salvage pathway. Collectively, our findings demonstrated that Se protected against ATO-mediated cardiotoxicity by antioxidant and anti-inflammatory effects via increasing the NAD+ pool in mice.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ATO:

Arsenic trioxide

Se:

Selenium

NAD + :

Nicotinamide adenine dinucleotide

CK:

Creatine kinase isoenzymes

LDH:

Lactate dehydrogenase

GSH:

Glutathione

cTnT:

Cardiac isoform of Troponin T

MDA:

Malondialdehyde

SOD:

Superoxide dismutase

CAT:

Catalase

IL-1β :

Interleukin 1β

IL-6:

Interleukin 6

TNF-α :

Tumor necrosis factor-α

EF:

Ejection fraction

NAMPT:

Nicotinamide phosphoribosyltransferase

IDO:

Indoleamine 2,3-dioxygenases

NADS:

Nicotinamide adenine dinucleotide synthase

NMNAT :

Nicotinamide/nicotinic acid mononucleotide adenylyltransferase

References

  1. Wang J, Hu W, Yang H, Chen F, Shu Y, Zhang G, Liu J, Liu Y, Li H, Guo L (2020) Arsenic concentrations, diversity and co-occurrence patterns of bacterial and fungal communities in the feces of mice under sub-chronic arsenic exposure through food. Environ Int 138:105600. https://doi.org/10.1016/j.envint.2020.105600

    Article  CAS  PubMed  Google Scholar 

  2. Jomova K, Jenisova Z, Feszterova M, Baros S, Liska J, Hudecova D, Rhodes CJ, Valko M (2011) Arsenic: toxicity, oxidative stress and human disease. J Appl Toxicol 31:95–107. https://doi.org/10.1002/jat.1649

    Article  CAS  PubMed  Google Scholar 

  3. James KA, Byers T, Hokanson JE, Meliker JR, Zerbe GO, Marshall JA (2015) Association between lifetime exposure to inorganic arsenic in drinking water and coronary heart disease in Colorado residents. Environ Health Perspect 123:128–134. https://doi.org/10.1289/ehp.1307839

    Article  PubMed  Google Scholar 

  4. Nigra AE, Moon KA, Jones MR, Sanchez TR, Navas-Acien A (2021) Urinary arsenic and heart disease mortality in NHANES 2003–2014. Environ Res 200:111387. https://doi.org/10.1016/j.envres.2021.111387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Alamolhodaei NS, Shirani K, Karimi G (2015) Arsenic cardiotoxicity: an overview. Environ Toxicol Pharmacol 40:1005–1014. https://doi.org/10.1016/j.etap.2015.08.030

    Article  CAS  PubMed  Google Scholar 

  6. Xu M, Rui D, Yan Y, Xu S, Niu Q, Feng G, Wang Y, Li S, Jing M (2017) Oxidative damage induced by arsenic in mice or rats: a systematic review and meta-analysis. Biol Trace Elem Res 176:154–175. https://doi.org/10.1007/s12011-016-0810-4

    Article  CAS  PubMed  Google Scholar 

  7. Ojeda ML, Nogales F, Del Carmen G-L, Carreras O (2022) Binge drinking during the adolescence period causes oxidative damage-induced cardiometabolic disorders: a possible ameliorative approach with selenium supplementation. Life Sci 301:120618. https://doi.org/10.1016/j.lfs.2022.120618

    Article  CAS  PubMed  Google Scholar 

  8. Kielczykowska M, Kocot J, Pazdzior M, Musik I (2018) Selenium - a fascinating antioxidant of protective properties. Adv Clin Exp Med 27:245–255. https://doi.org/10.17219/acem/67222

    Article  PubMed  Google Scholar 

  9. Bomer N, Grote Beverborg N, Hoes MF, Streng KW, Vermeer M, Dokter MM, IJ J, Anker SD, Cleland JGF, Hillege HL, Lang CC, Ng LL, Samani NJ, Tromp J, van Veldhuisen DJ, Touw DJ, Voors AA, van der Meer P (2020) Selenium and outcome in heart failure. Eur J Heart Fail 22:1415–1423. https://doi.org/10.1002/ejhf.1644

    Article  CAS  PubMed  Google Scholar 

  10. Wang X, Yang B, Cao HL, Wang RY, Lu ZY, Chi RF, Li B (2021) Selenium supplementation protects against lipopolysaccharide-induced heart injury via sting pathway in mice. Biol Trace Elem Res 199:1885–1892. https://doi.org/10.1007/s12011-020-02295-5

    Article  CAS  PubMed  Google Scholar 

  11. Yang HB, Lu ZY, Yuan W, Li WD, Mao S (2022) Selenium attenuates doxorubicin-induced cardiotoxicity through Nrf2-NLRP3 pathway. Biol Trace Elem Res 200:2848–2856. https://doi.org/10.1007/s12011-021-02891-z

    Article  CAS  PubMed  Google Scholar 

  12. Ren Z, Wu Q, Deng H, Yu Y, Tang W, Deng Y, Zhu L, Wang Y, Deng J (2021) Effects of selenium on the immunotoxicity of subacute arsenic poisoning in chickens. Biol Trace Elem Res 199:4260–4272. https://doi.org/10.1007/s12011-020-02558-1

    Article  CAS  PubMed  Google Scholar 

  13. Adedara IA, Fabunmi AT, Ayenitaju FC, Atanda OE, Adebowale AA, Ajayi BO, Owoeye O, Rocha JBT, Farombi EO (2020) Neuroprotective mechanisms of selenium against arsenic-induced behavioral impairments in rats. Neurotoxicology 76:99–110. https://doi.org/10.1016/j.neuro.2019.10.009

    Article  CAS  PubMed  Google Scholar 

  14. Ren Z, Deng H, Deng Y, Tang W, Wu Q, Zuo Z, Cui H, Hu Y, Yu S, Xu SY, Deng J (2021) Effects of selenium on arsenic-induced liver lesions in broilers. Biol Trace Elem Res 199:1080–1089. https://doi.org/10.1007/s12011-020-02222-8

    Article  CAS  PubMed  Google Scholar 

  15. Galli U, Colombo G, Travelli C, Tron GC, Genazzani AA, Grolla AA (2020) Recent advances in NAMPT inhibitors: a novel immunotherapic strategy. Front Pharmacol 11:656. https://doi.org/10.3389/fphar.2020.00656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Garten A, Schuster S, Penke M, Gorski T, de Giorgis T, Kiess W (2015) Physiological and pathophysiological roles of NAMPT and NAD metabolism. Nat Rev Endocrinol 11:535–546. https://doi.org/10.1038/nrendo.2015.117

    Article  CAS  PubMed  Google Scholar 

  17. Zhou CC, Yang X, Hua X, Liu J, Fan MB, Li GQ, Song J, Xu TY, Li ZY, Guan YF, Wang P, Miao CY (2016) Hepatic NAD(+) deficiency as a therapeutic target for non-alcoholic fatty liver disease in ageing. Br J Pharmacol 173:2352–2368. https://doi.org/10.1111/bph.13513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhou B, Wang DD, Qiu Y, Airhart S, Liu Y, Stempien-Otero A, O’Brien KD, Tian R (2020) Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure. J Clin Invest 130:6054–6063. https://doi.org/10.1172/JCI138538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Li, L, Xu W, Zhang L (2021) KLF15 Regulates oxidative stress response in cardiomyocytes through NAD(). Metabolites 11 https://doi.org/10.3390/metabo11090620

  20. Zheng D, Zhang Y, Zheng M, Cao T, Wang G, Zhang L, Ni R, Brockman J, Zhong H, Fan GC, Peng T (2019) Nicotinamide riboside promotes autolysosome clearance in preventing doxorubicin-induced cardiotoxicity. Clin Sci (Lond) 133:1505–1521. https://doi.org/10.1042/CS20181022

    Article  CAS  PubMed  Google Scholar 

  21. Wang XY, Wang JZ, Gao L, Zhang FY, Wang Q, Liu KJ, Xiang B (2017) Inhibition of nicotinamide phosphoribosyltransferase and depletion of nicotinamide adenine dinucleotide contribute to arsenic trioxide suppression of oral squamous cell carcinoma. Toxicol Appl Pharmacol 331:54–61. https://doi.org/10.1016/j.taap.2017.05.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zheng B, Yang Y, Li J, Li J, Zuo S, Chu X, Xu S, Ma D, Chu L (2021) Magnesium isoglycyrrhizinate alleviates arsenic trioxide-induced cardiotoxicity: contribution of Nrf2 and TLR4/NF-kappaB signaling pathway. Drug Des Devel Ther 15:543–556. https://doi.org/10.2147/DDDT.S296405

    Article  PubMed  PubMed Central  Google Scholar 

  23. Messarah M, Klibet F, Boumendjel A, Abdennour C, Bouzerna N, Boulakoud MS, El Feki A (2012) Hepatoprotective role and antioxidant capacity of selenium on arsenic-induced liver injury in rats. Exp Toxicol Pathol 64:167–174. https://doi.org/10.1016/j.etp.2010.08.002

    Article  CAS  PubMed  Google Scholar 

  24. Chen YC, Lin-Shiau SY, Lin JK (1998) Involvement of reactive oxygen species and caspase 3 activation in arsenite-induced apoptosis. J Cell Physiol 177:324–333. https://doi.org/10.1002/(SICI)1097-4652(199811)177:2%3c324::AID-JCP14%3e3.0.CO;2-9

    Article  CAS  PubMed  Google Scholar 

  25. Liang Y, Zheng B, Li J, Shi J, Chu L, Han X, Chu X, Zhang X, Zhang J (2020) Crocin ameliorates arsenic trioxideinduced cardiotoxicity via Keap1-Nrf2/HO-1 pathway: reducing oxidative stress, inflammation, and apoptosis. Biomed Pharmacother 131:110713. https://doi.org/10.1016/j.biopha.2020.110713

    Article  CAS  PubMed  Google Scholar 

  26. Sun TL, Liu Z, Qi ZJ, Huang YP, Gao XQ, Zhang YY (2016) (-)-Epigallocatechin-3-gallate (EGCG) attenuates arsenic-induced cardiotoxicity in rats. Food Chem Toxicol 93:102–110. https://doi.org/10.1016/j.fct.2016.05.004

    Article  CAS  PubMed  Google Scholar 

  27. Breton M, Costemale-Lacoste JF, Li Z, Lafuente-Lafuente C, Belmin J, Mericskay M (2020) Blood NAD levels are reduced in very old patients hospitalized for heart failure. Exp Gerontol 139:111051. https://doi.org/10.1016/j.exger.2020.111051

    Article  CAS  PubMed  Google Scholar 

  28. Abdellatif M, Sedej S, Kroemer G (2021) NAD(+) Metabolism in cardiac health, Aging, and Disease. Circulation 144:1795–1817. https://doi.org/10.1161/CIRCULATIONAHA.121.056589

    Article  CAS  PubMed  Google Scholar 

  29. Chiao YA, Chakraborty AD, Light CM, Tian R, Sadoshima J, Shi X, Gu H, Lee CF (2021) NAD(+) redox imbalance in the heart exacerbates diabetic cardiomyopathy. Circ Heart Fail 14:e008170. https://doi.org/10.1161/CIRCHEARTFAILURE.120.008170

    Article  PubMed  PubMed Central  Google Scholar 

  30. Khadka D, Kim HJ, Oh GS, Shen A, Lee S, Lee SB, Sharma S, Kim SY, Pandit A, Choe SK, Kwak TH, Yang SH, Sim H, Eom GH, Park R, So HS (2018) Augmentation of NAD(+) levels by enzymatic action of NAD(P)H quinone oxidoreductase 1 attenuates adriamycin-induced cardiac dysfunction in mice. J Mol Cell Cardiol 124:45–57. https://doi.org/10.1016/j.yjmcc.2018.10.001

    Article  CAS  PubMed  Google Scholar 

  31. Tong D, Schiattarella GG, Jiang N, Altamirano F, Szweda PA, Elnwasany A, Lee DI, Yoo H, Kass DA, Szweda LI, Lavandero S, Verdin E, Gillette TG, Hill JA (2021) NAD(+) repletion reverses heart failure with preserved ejection fraction. Circ Res 128:1629–1641. https://doi.org/10.1161/CIRCRESAHA.120.317046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Feng, D, Xu D, Murakoshi N, Tajiri K, Qin R, Yonebayashi S, Okabe Y, Li S, Yuan Z, Aonuma K, Ieda M (2020) Nicotinamide phosphoribosyltransferase (Nampt)/nicotinamide adenine dinucleotide (NAD) axis suppresses atrial fibrillation by modulating the calcium handling pathway. Int J Mol Sci 21 https://doi.org/10.3390/ijms21134655

  33. Oka SI, Byun J, Huang CY, Imai N, Ralda G, Zhai P, Xu X, Kashyap S, Warren JS, Alan Maschek J, Tippetts TS, Tong M, Venkatesh S, Ikeda Y, Mizushima W, Kashihara T, Sadoshima J (2021) Nampt potentiates antioxidant defense in diabetic cardiomyopathy. Circ Res 129:114–130. https://doi.org/10.1161/CIRCRESAHA.120.317943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by The Program of Yingshang ChengDong Hospital (201903127).

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Authors and Affiliations

  1. Department of Cardiology, Yingshang ChengDong Hospital, Yingli Road, Fuyang, 236000, China

    Hai-Bing Yang & Shang Mao

  2. Department of Cardiology, Affiliated Hospital of Jiangsu University, Jie Fang Road 438, Zhenjiang, 212001, China

    Wei Yuan & Wei-Dong Li

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Contributions

Hai-Bing Yang provided funding and designed research; Hai-Bing Yang and Wei Yuan performed experiments; Hai-Bing Yang and Wei Yuan analyzed data and wrote the manuscript; Shang Mao checked the manuscript. All authors contributed with productive discussions and knowledge to the final version of this manuscript.

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Correspondence to Hai-Bing Yang.

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Yang, HB., Yuan, W., Li, WD. et al. Selenium Supplementation Protects Against Arsenic-Trioxide-Induced Cardiotoxicity Via Reducing Oxidative Stress and Inflammation Through Increasing NAD+ Pool. Biol Trace Elem Res 201, 3941–3950 (2023). https://doi.org/10.1007/s12011-022-03478-y

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