槲皮素以 hERG 钾通道为目标,是心脏的克星。

IF 2.1 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Iranian Journal of Basic Medical Sciences Pub Date : 2024-01-01 DOI:10.22038/ijbms.2024.77846.16848
Zihao Lu, Shuwen Li, Rui Wei, Wenwen Li, Yuqian Huang, Tingting Yang, Meng Yan
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引用次数: 0

摘要

研究目的槲皮素是一种植物黄酮类化合物,具有抗氧化、抗炎和抗癌等药理作用。然而,有关其潜在毒性的信息却很有限。之前的一项研究表明,槲皮素可抑制人类醚一戈相关基因(hERG,又称 KCNH2)电流,从而可能导致长 QT 综合征、心搏过速(TdP),甚至心源性猝死。本研究旨在探讨槲皮素对 hERG 的影响及其潜在机制。材料与方法:采用膜片钳技术评估 hERG 电流和动作电位持续时间(APD)。采用分子对接法阐明槲皮素与 hERG 的结合位点。转染野生型或突变型质粒用于验证分子对接的结果。采用 Western 印迹法测定 hERG、转录因子 SP1、分子伴侣 HSP70 和 HSP90、磷酸化 E3 泛素连接酶 p-Nedd4-2、血清和糖皮质激素诱导激酶 (SGK1) 和磷脂酰肌醇 3- 激酶 (PI3K) 的表达水平。免疫沉淀用于评估 hERG 泛素化:结果:槲皮素通过与 F656 氨基酸残基结合急性阻断了 hERG 电流,随后加速了通道失活。槲皮素长期孵育可通过抑制 PI3K/SGK1 信号通路加速 Nedd4-2 介导的 hERG 通道泛素化降解。此外,30 μM 槲皮素可显著延长人诱导多能干细胞衍生心肌细胞(hiPS-CMs)的 APD:槲皮素有导致心律失常的潜在风险,这为槲皮素作为药物的使用和开发提供了有用的信息。
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Quercetin is a foe in the heart by targeting the hERG potassium channel.

Objectives: 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.

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来源期刊
Iranian Journal of Basic Medical Sciences
Iranian Journal of Basic Medical Sciences MEDICINE, RESEARCH & EXPERIMENTAL-PHARMACOLOGY & PHARMACY
CiteScore
4.00
自引率
4.50%
发文量
142
审稿时长
6-12 weeks
期刊介绍: The Iranian Journal of Basic Medical Sciences (IJBMS) is a peer-reviewed, monthly publication by Mashhad University of Medical Sciences (MUMS), Mashhad, Iran . The Journal of "IJBMS” is a modern forum for scientific communication. Data and information, useful to investigators in any discipline in basic medical sciences mainly including Anatomical Sciences, Biochemistry, Genetics, Immunology, Microbiology, Pathology, Pharmacology, Pharmaceutical Sciences, and Physiology, will be published after they have been peer reviewed. This will also include reviews and multidisciplinary research.
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