Quercetin is a foe in the heart by targeting the hERG potassium channel

Document Type : Original Article

Authors

1 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China

2 Department of Pharmacy, Jiangsu Province Official Hospital

10.22038/ijbms.2024.77846.16848

Abstract

Objective(s): Quercetin is a plant flavonoid known for its pharmacological activities, such as antioxidant, anti-inflammatory, and anti-cancer properties. However, there is limited information available regarding its potential toxicities. A previous study showed that quercetin can inhibit human ether-a-go-related gene (hERG, also named KCNH2) currents, which may lead to long QT syndrome, torsade de pointes (TdP), and even sudden cardiac death. This study aimed to investigate the effects of quercetin on hERG and its potential mechanism.
Materials and Methods: hERG currents and action potential duration (APD) were assessed using the patch clamp technique. Molecular docking was employed to elucidate the binding sites between quercetin and hERG. Transfection of wild-type or mutant plasmids was used to verify the results of molecular docking. Western blot was performed to determine the expression levels of hERG, transcription factor SP1, molecular chaperones HSP70 and HSP90, phosphorylated E3 ubiquitin ligase p-Nedd4-2, serum- and glucocorticoid-inducible kinase (SGK1), and phosphatidylinositol 3-kinase (PI3K). Immunoprecipitation was conducted to evaluate hERG ubiquitination.
Results: Quercetin acutely blocked hERG current by binding to F656 amino acid residue, subsequently accelerating channel inactivation. Long-term incubation of quercetin accelerates Nedd4-2-mediated ubiquitination degradation of hERG channels by inhibiting the PI3K/SGK1 signaling pathway. Moreover, the APD of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) is significantly prolonged by 30 μM quercetin.
Conclusion: Quercetin has a potential risk of proarrhythmia, which provided useful information for the usage and development of quercetin as a medication.

Keywords

Main Subjects

References

1. Alexander C, Bishop MJ, Gilchrist RJ, Burton FL, Smith GL, Myles RC. Initiation of ventricular arrhythmia in the acquired long QT syndrome. Cardiovasc Res 2023; 119: 465-476.
2. Yan M, Feng L, Shi Y, Wang J, Liu Y, Li F, et al. Mechanism of As2O3-induced action potential prolongation and using hiPS-CMs to evaluate the rescue efficacy of drugs with different rescue mechanism. Toxicol Sci 2017; 158:379-390.
3. Cai C, Guo P, Zhou Y, Zhou J, Wang Q, Zhang F, et al. Deep learning-based prediction of drug-induced cardiotoxicity. J Chem Inf Model 2019; 59:1073-1084.
4. Saponara S, Fusi F, Iovinelli D, Ahmed A, Trezza A, Spiga O, et al. Flavonoids and hERG channels: Friends or foes? Eur J Pharmacol 2021; 899:174030.
5. Sun X, Xu B, Xue Y, Li H, Zhang H, Zhang Y, et al. Characterization and structure-activity relationship of natural flavonoids as hERG K(+) channel modulators. Int Immunopharmacol 2017; 45: 187-193.
6. Trott O, Olson AJ. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31:455-461.
7. Sanner MF. Python: a programming language for software integration and development. J Mol Graph Model 1999; 17:57-61.
8. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 2009; 30:2785-2791.
9. Kamens J. The Addgene repository: An international nonprofit plasmid and data resource. Nucleic Acids Res 2015; 43: D1152-1157.
10. Boots AW, Li H, Schins RP, Duffin R, Heemskerk JW, Bast A, et al. The quercetin paradox. Toxicol Appl Pharmacol 2007; 222: 89-96.
11. Cunningham P, Patton E, VanderVeen BN, Unger C, Aladhami A, Enos RT, et al. Sub-chronic oral toxicity screening of quercetin in mice. BMC Complement Med Ther 2022; 22:279.
12. Sanson C, Boukaiba R, Houtmann S, Maizieres MA, Fouconnier S, Partiseti M, et al. The grapefruit polyphenol naringenin inhibits multiple cardiac ion channels. Naunyn Schmiedebergs Arch Pharmacol 2022; 395:735-740.
13. Liu Y, Xu XH, Liu Z, Du XL, Chen KH, Xin X, et al. Effects of the natural flavone trimethylapigenin on cardiac potassium currents. Biochem Pharmacol 2012; 84:498-506.
14. Nogawa H, Kawai T. hERG trafficking inhibition in drug-induced lethal cardiac arrhythmia. Eur J Pharmacol 2014; 741:336-339.
15. Staudacher I, Schweizer PA, Katus HA, Thomas D. hERG: protein trafficking and potential for therapy and drug side effects. Curr Opin Drug Discov Devel 2010; 13:23-30.
16. Yan M, Zhang K, Shi Y, Feng L, Lv L, Li B. Mechanism and pharmacological rescue of berberine-induced hERG channel deficiency. Drug Des Devel Ther 2015; 9:5737-5747.
17. Duan JJ, Ma JH, Zhang PH, Wang XP, Zou AR, Tu DN. Verapamil blocks HERG channel by the helix residue Y652 and F656 in the S6 transmembrane domain. Acta Pharmacol Sin 2007; 28:959-967.
18. Lees-Miller JP, Duan Y, Teng GQ, Duff HJ. Molecular determinant of high-affinity dofetilide binding to HERG1 expressed in Xenopus oocytes: involvement of S6 sites. Mol Pharmacol 2000; 57:367-374.
19. Macdonald LC, Kim RY, Kurata HT, Fedida D. Probing the molecular basis of hERG drug block with unnatural amino acids. Sci Rep 2018; 8:289-298.
20. Liu Y, Xu X, Zhang Y, Li M, Guo J, Yan C, et al. Thioridazine induces cardiotoxicity via reactive oxygen species-mediated hERG channel deficiency and L-type calcium channel activation. Oxid Med Cell Longev 2020; 2020: 3690123-3690139.
21. Zhan G, Wang F, Ding YQ, Li XH, Li YX, Zhao ZR, et al. Rutaecarpine targets hERG channels and participates in regulating electrophysiological properties leading to ventricular arrhythmia. J Cell Mol Med 2021; 25:4938-4949.
22. Feng PF, Zhang B, Zhao L, Fang Q, Liu Y, Wang JN, et al. Intracellular mechanism of rosuvastatin-induced decrease in mature hERG protein expression on membrane. Mol Pharm 2019; 16:1477-1488.
23. Shi YQ, Yan CC, Zhang X, Yan M, Liu LR, Geng HZ, et al. Mechanisms underlying probucol-induced hERG-channel deficiency. Drug Des Devel Ther 2015; 9: 3695-3704.
24. Zhang K, Zhi D, Huang T, Gong Y, Yan M, Liu C, et al. Berberine induces hERG channel deficiency through trafficking inhibition. Cell Physiol Biochem 2014; 34:691-702.
25. Vandenberg JI, Perry MD, Perrin MJ, Mann SA, Ke Y, Hill AP. hERG K(+) channels: Structure, function, and clinical significance. Physiol Rev 2012; 92:1393-1478.
26. Lin H, Xiao J, Luo X, Wang H, Gao H, Yang B, et al. Overexpression HERG K(+) channel gene mediates cell-growth signals on activation of oncoproteins SP1 and NF-kappaB and inactivation of tumor suppressor Nkx3.1. J Cell Physiol 2007; 212: 137-147.
27. Yu D, Lv L, Fang L, Zhang B, Wang J, Zhan G, et al. Inhibitory effects and mechanism of dihydroberberine on hERG channels expressed in HEK293 cells. PLoS One 2017; 12: e0181823-0181841.
28. Cui X, Sun J, Li C, Qiu S, Shi C, Ma J, et al. Downregulation of hERG channel expression by tyrosine kinase inhibitors nilotinib and vandetanib predominantly contributes to arrhythmogenesis. Toxicol Lett 2022; 365:11-23.
29. Li P, Tian X, Wang G, Jiang E, Li Y, Hao G. Acute osimertinib exposure induces electrocardiac changes by synchronously inhibiting the currents of cardiac ion channels. Front Pharmacol 2023; 14: 1177003-1177013.
30. Wu T, Chen Y, Yang C, Lu M, Geng F, Guo J, et al. Systematical evaluation of the structure-cardiotoxicity relationship of 7-azaindazole-based PI3K inhibitors designed by bioisosteric approach. Cardiovasc Toxicol 2023; 23:364-376.
31. Zhang Y, Wang H, Wang J, Han H, Nattel S, Wang Z. Normal function of HERG K+ channels expressed in HEK293 cells requires basal protein kinase B activity. FEBS Lett 2003; 534:125-132.
32. Huang YT, Hwang JJ, Lee PP, Ke FC, Huang JH, Huang CJ, et al. Effects of luteolin and quercetin, inhibitors of tyrosine kinase, on cell growth and metastasis-associated properties in A431 cells overexpressing epidermal growth factor receptor. Br J Pharmacol 1999; 128:999-1010.
33. Andersen MN, Krzystanek K, Petersen F, Bomholtz SH, Olesen SP, Abriel H, et al. A phosphoinositide 3-kinase (PI3K)-serum- and glucocorticoid-inducible kinase 1 (SGK1) pathway promotes Kv7.1 channel surface expression by inhibiting Nedd4-2 protein. J Biol Chem 2013; 288:36841-36854.
34. Deng W, Li CY, Tong J, He J, Zhao Y, Wang DX. Insulin ameliorates pulmonary edema through the upregulation of epithelial sodium channel via the PI3K/SGK1 pathway in mice with lipopolysaccharide‑induced lung injury. Mol Med Rep 2019; 19: 1665-1677.
35. Wang H, You G. SGK1/Nedd4-2 signaling pathway regulates the activity of human organic anion transporters 3. Biopharm Drug Dispos 2017; 38:449-457.
36. Zhang H, Fu T, Sun J, Zou S, Qiu S, Zhang J, et al. Pharmacological suppression of Nedd4-2 rescues the reduction of Kv11.1 channels in pathological cardiac hypertrophy. Front Pharmacol 2022; 13: 942769-942785.
37. Ivashchenko CY, Pipes GC, Lozinskaya IM, Lin Z, Xiaoping X, Needle S, et al. Human-induced pluripotent stem cell-derived cardiomyocytes exhibit temporal changes in phenotype. Am J Physiol Heart Circ Physiol 2013; 305:H913-922.
38. Paci M, Hyttinen J, Rodriguez B, Severi S. Human induced pluripotent stem cell-derived versus adult cardiomyocytes: An in silico electrophysiological study on effects of ionic current block. Br J Pharmacol 2015; 172:5147-5160.
39. Monteiro da Rocha A, Allan A, Block T, Creech J, Herron TJ. High-throughput cardiotoxicity screening using mature human induced pluripotent stem cell-derived cardiomyocyte monolayers. J Vis Exp 2023; 193: e64364.
40. Ellis BW, Traktuev DO, Merfeld-Clauss S, Can UI, Wang M, Bergeron R, et al. Adipose stem cell secretome markedly improves rodent heart and human induced pluripotent stem cell-derived cardiomyocyte recovery from cardioplegic transport solution exposure. Stem Cells 2021; 39:170-182.
41. Ortiz-Andrade R, Araujo-Leon JA, Sanchez-Recillas A, Navarrete-Vazquez G, Gonzalez-Sanchez AA, Hidalgo-Figueroa S, et al. Toxicological screening of four bioactive citroflavonoids: In vitro, in vivo, and in silico approaches. Molecules 2020; 25: 5959-5970.
42. Burak C, Brull V, Langguth P, Zimmermann BF, Stoffel-Wagner B, Sausen U, et al. Higher plasma quercetin levels following oral administration of an onion skin extract compared with pure quercetin dihydrate in humans. Eur J Nutr 2017; 56:343-353.
43. Andres S, Pevny S, Ziegenhagen R, Bakhiya N, Schafer B, Hirsch-Ernst KI, et al. Safety aspects of the use of quercetin as a dietary supplement. Mol Nutr Food Res 2018; 62: 1-10.
44. Hard GC, Seely JC, Betz LJ, Hayashi SM. Re-evaluation of the kidney tumors and renal histopathology occurring in a 2-year rat carcinogenicity bioassay of quercetin. Food Chem Toxicol 2007; 45:600-608.
 
Iranian Journal of Basic Medical Sciences
Volume 27, Issue 11
November 2024
Pages 1397-1404

Files

Share

How to cite

Statistics