Quercetin is a foe in the heart by targeting the hERG potassium channel
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 ethe...
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Mashhad University of Medical Sciences
2024-11-01
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| Series: | Iranian Journal of Basic Medical Sciences |
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| Online Access: | https://ijbms.mums.ac.ir/article_24662_5c98f1d37d2bed4c0c52260b80109426.pdf |
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| author | Zihao Lu Shuwen Li Rui Wei Wenwen Li Yuqian Huang Tingting Yang Meng Yan |
| author_facet | Zihao Lu Shuwen Li Rui Wei Wenwen Li Yuqian Huang Tingting Yang Meng Yan |
| author_sort | Zihao Lu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-3b65e908b48e437bac5d1c2f24b0aa1d |
| institution | Matheson Library |
| issn | 2008-3866 2008-3874 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Mashhad University of Medical Sciences |
| record_format | Article |
| series | Iranian Journal of Basic Medical Sciences |
| spelling | doaj-art-3b65e908b48e437bac5d1c2f24b0aa1d2025-07-27T09:50:45ZengMashhad University of Medical SciencesIranian Journal of Basic Medical Sciences2008-38662008-38742024-11-0127111397140410.22038/ijbms.2024.77846.1684824662Quercetin is a foe in the heart by targeting the hERG potassium channelZihao Lu0Shuwen Li1Rui Wei2Wenwen Li3Yuqian Huang4Tingting Yang5Meng Yan6Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, ChinaJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, ChinaDepartment of Pharmacy, Jiangsu Province Official HospitalJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, ChinaJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, ChinaJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, ChinaJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, ChinaObjective(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.https://ijbms.mums.ac.ir/article_24662_5c98f1d37d2bed4c0c52260b80109426.pdfdegradationkcnh2long qt syndromenedd4ubiquitination |
| spellingShingle | Zihao Lu Shuwen Li Rui Wei Wenwen Li Yuqian Huang Tingting Yang Meng Yan Quercetin is a foe in the heart by targeting the hERG potassium channel Iranian Journal of Basic Medical Sciences degradation kcnh2 long qt syndrome nedd4 ubiquitination |
| title | Quercetin is a foe in the heart by targeting the hERG potassium channel |
| title_full | Quercetin is a foe in the heart by targeting the hERG potassium channel |
| title_fullStr | Quercetin is a foe in the heart by targeting the hERG potassium channel |
| title_full_unstemmed | Quercetin is a foe in the heart by targeting the hERG potassium channel |
| title_short | Quercetin is a foe in the heart by targeting the hERG potassium channel |
| title_sort | quercetin is a foe in the heart by targeting the herg potassium channel |
| topic | degradation kcnh2 long qt syndrome nedd4 ubiquitination |
| url | https://ijbms.mums.ac.ir/article_24662_5c98f1d37d2bed4c0c52260b80109426.pdf |
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