Article(id=1308817728916517109, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308817633789698171, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2025-0746, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1751212800000, receivedDateStr=2025-06-30, revisedDate=1762617600000, revisedDateStr=2025-11-09, acceptedDate=null, acceptedDateStr=null, onlineDate=1789976063230, onlineDateStr=2026-09-21, pubDate=1770825600000, pubDateStr=2026-02-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1789976063230, onlineIssueDateStr=2026-09-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1789976063230, creator=13701087609, updateTime=1789976063230, updator=13701087609, issue=Issue{id=1308817633789698171, tenantId=1146029695717560320, journalId=1189982191388893191, year='2026', volume='61', issue='2', pageStart='321', pageEnd='676', issueExtLink='null', onlineDate='null', pubDate='1770825600000', pubDateStr='2026-02-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1789976040551, creator='13701087609', updateTime=1789984264575, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1308852127921963901, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308817633789698171, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1308852127921963902, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308817633789698171, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=486, endPage=493, ext={EN=ArticleExt(id=1308817729143009526, articleId=1308817728916517109, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Application of hiPSC-CMs model to compare the reversal effects and mechanisms of different drugs on thioridazine-induced acLQTS, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Drug targeting of the human ether-à-go-go-related gene (hERG)-encoded rapid delayed rectifier potassium channel induces acquired long QT syndrome (acLQTS), predisposing individuals to life-threatening arrhythmias. Previous studies demonstrate that the antipsychotic agent thioridazine (THIO) triggers acLQTS. Our findings aimed to elucidate the underlying mechanisms of the therapeutic effects against drug-induced cardiotoxicity. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) integrated with multi-electrode arrays (MEA) and optical mapping technology, we evaluated and compared the efficacy of tanshinone IIA (TANIIA), propranolol (Prop) and resveratrol (Res) in reversing THIO-induced prolongation of action potential duration (APD) and field potential duration (all animal experiments were conducted in accordance with the Animal Care Guidelines of Harbin Medical University and were approved by the Ethics Committee of Harbin Medical University, the approval number is IRB3020622). The results showed that TANIIA significantly reversed the THIO-induced prolongation of APD90, APD50, and field potential, whereas neither Prop nor Res counteracted this effect. Building on these results, we further explored the mechanistic basis and molecular targets underlying TANIIA's reversal effects. Western blot and whole-cell patch-clamp demonstrated that TANIIA restored hERG protein expression downregulated by THIO and rescued its channel trafficking defects and rescued channel trafficking defects. Mechanistically, TANIIA attenuated THIO-induced aberrant interactions between hERG and the calnexin, thereby rectifying impaired channel folding and trafficking. Concurrently, TANIIA substantially reduced THIO-induced L-type calcium current. In conclusion, TANIIA ameliorates THIO-induced acLQTS by up regulating hERG current expression and down regulating L-type calcium current. These findings highlight its therapeutic potential of drug-induced acLQTS for clinical.

, authors=Jia-xin LI1, Yan LIU1, Xiao-xu LI1, Hai-ying HONG1, Yu-yan ZHOU1, Ying SONG1, Bao-xin LI1, *, Pan FAN2, *, authorsList=Jia-xin LI, Yan LIU, Xiao-xu LI, Hai-ying HONG, Yu-yan ZHOU, Ying SONG, Bao-xin LI, Pan FAN, authorCompany=null, correspAuthors=Bao-xin LI, Pan FAN, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2026 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1308817732045467907, articleId=1308817728916517109, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=应用hiPSC-CMs细胞模型比较不同药物对硫利达嗪诱发的acLQTS的逆转作用及机制, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

药物靶向心脏人类ether-à-go-go相关基因(human ether-à-go-go-related gene, hERG) 编码的快速延迟整流钾通道易诱发获得性长QT综合征(acquired long QT syndrome, acLQTS), 使患者发生危及生命的心律失常。抗精神失常药硫利达嗪(thioridazine, THIO) 在临床应用时产生诱发acLQTS的心脏毒性, 如何逆转并探索可能的机制即为本研究的目的。本研究应用人诱导多能干细胞衍生的心肌细胞(human induced pluripotent stem cell derived cardiomyocytes, hiPSC-CMs) 模型, 结合微电极阵列(multi-electrode array, MEA)、高分辨荧光标测技术评价比较了丹参酮ⅡA (tanshinone IIA, TANIIA)、普萘洛尔(propranolol, Prop)、白藜芦醇(resveratrol, Res) 对硫利达嗪引起的动作电位时程(action potential duration, APD)、场电位延长的逆转作用(所有动物实验均按照哈尔滨医科大学动物操作准则进行并得到哈尔滨医科大学伦理委员会的批准, 伦理号-IRB3020622)。结果显示, 丹参酮能够明显逆转硫利达嗪延长的APD90、APD50及场电位, 而普萘洛尔和白藜芦醇两药没有逆转硫利达嗪导致APD及场电位的延长作用。基于以上结果, 本研究进一步探索丹参酮ⅡA发挥逆转作用的机制及靶点。Western blot及全细胞膜片钳检测结果证实, 丹参酮ⅡA对硫利达嗪抑制的hERG蛋白具有明显的拯救作用, 其机制是丹参酮ⅡA通过减弱硫利达嗪造成的hERG蛋白与钙连蛋白(calnexin) 的相互作用, 拯救了硫利达嗪诱发的hERG通道蛋白折叠转运障碍, 同时hERG电流也增加; 此外丹参酮ⅡA明显减少了硫利达嗪所激活的钙电流。综上, 丹参酮ⅡA可以通过上调hERG蛋白、hERG电流及下调钙电流, 最终逆转硫利达嗪诱发的acLQTS, 有望成为临床上治疗acLQTS的有效药物。

, authors=李加欣1, 刘妍1, 李晓旭1, 洪海颖1, 周雨妍1, 宋莹1, 李宝馨1, *, 樊攀2, *, authorsList=李加欣, 刘妍, 李晓旭, 洪海颖, 周雨妍, 宋莹, 李宝馨, 樊攀, authorCompany=null, correspAuthors=李宝馨, 樊攀, authorNote=

#

共同第一作者.

作者贡献:

李加欣负责实验研究和文章撰写; 刘妍负责具体实验方案设计和实验指导; 李晓旭负责实验指导与研究; 洪海颖、周雨妍、宋莹负责实验研究; 樊攀负责图表制作、文章修改、审核及临床合作研究; 李宝馨负责课题设计、文章修改、审核及提供基金。

, correspAuthorsNote=
李宝馨, Tel: 86-451-86671354, E-mail:
樊攀, Tel: 86-451-86605704, E-mail:
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A: APD50 and APD90 representative maps; B: Statistical analysis of APD50 and APD90 of optical mapping. n = 5, $ \overline{x} $ ± SEM. *P < 0.05 vs Ctrl; #P < 0.05 vs THIO. THIO: Thioridazine; APD: Action potential duration; Prop: Propranolol; TANIIA: Tanshinone IIA; Res: Resveratrol, figureFileSmall=jzON0lo4oRTuLm5jhlooPg==, figureFileBig=Bq6VyIRH9kC/MjPJPoZp+A==, tableContent=null), ArticleFig(id=1308817891563237860, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817728916517109, language=EN, label=null, caption=null, figureFileSmall=E2bI46uLcX5PEVPwvcQzyw==, figureFileBig=z3czag27L9nPHSFEgQmUqA==, tableContent=null), ArticleFig(id=1308817891626152421, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817728916517109, language=CN, label=Fig.2, caption=Effects of THIO and reversal drugs on the field potential of hiPSC-CMs. A-F: Representative field potentials of hiPSC-CMs under the following respective drug administration conditions: Ctrl group (A), 3 μmol·L-1 THIO group (B), 3 μmol·L-1 THIO + 10 μmol·L-1 TANIIA group (C), 3 μmol·L-1 THIO + 10 μmol·L-1 Prop group (D), and 3 μmol·L-1 THIO + 10 μmol·L-1 Res group (E). n = 3, $ \overline{x} $ ± SEM. *P < 0.05 vs Ctrl; #P < 0.05 vs THIO. hiPSC-CMs: Human induced pluripotent stem cell-derived cardiomyocytes; FPDc: Field potential duration correction, figureFileSmall=E2bI46uLcX5PEVPwvcQzyw==, figureFileBig=z3czag27L9nPHSFEgQmUqA==, tableContent=null), ArticleFig(id=1308817893316456934, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817728916517109, language=EN, label=null, caption=null, figureFileSmall=9oztjoVjDdh5KKYy4YArFQ==, figureFileBig=1L+0w9SC29Z+BHbdX64w1g==, tableContent=null), ArticleFig(id=1308817893391954407, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817728916517109, language=CN, label=Fig.3, caption=Rescue effect of TANIIA on THIO-inhibited hERG protein. Western blot results (A) and statistics (B) for hERG expression (incubation for 24 h). THIO significantly reduced 155 kDa of the hERG channel. TANIIA rescues hERG protein inhibited by THIO. n = 5, $ \overline{x} $ ± SEM. *P < 0.05 vs Ctrl; #P < 0.05 vs THIO, figureFileSmall=9oztjoVjDdh5KKYy4YArFQ==, figureFileBig=1L+0w9SC29Z+BHbdX64w1g==, tableContent=null), ArticleFig(id=1308817893480034792, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817728916517109, language=EN, label=null, caption=null, figureFileSmall=g/HRNehmdmBWQ3exdhOVDg==, figureFileBig=hqBx1xVUvm+XXZyuyZ9XgA==, tableContent=null), ArticleFig(id=1308817893542949353, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817728916517109, language=CN, label=Fig.4, caption=Rescue effect of TANIIA on THIO-inhibited hERG channel currents. A: Protocol and examples on the hERG current under Ctrl, THIO-treated and drug-treated conditions; B: I-V curve of the hERG current. THIO reduced the hERG current. TANIIA rescues THIO-inhibited hERG currents. n =11, $ \overline{x} $ ± SEM. *P < 0.05 vs Ctrl; #P < 0.05 vs THIO, figureFileSmall=g/HRNehmdmBWQ3exdhOVDg==, figureFileBig=hqBx1xVUvm+XXZyuyZ9XgA==, tableContent=null), ArticleFig(id=1308817893626835434, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817728916517109, language=EN, label=null, caption=null, figureFileSmall=X4+WNQ/PBg9GZz2pqiedqg==, figureFileBig=4QPDb7vmaUOlpkICAN2yhw==, tableContent=null), ArticleFig(id=1308817893706527211, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817728916517109, language=CN, label=Fig.5, caption=The effect of co-incubation of TANIIA and THIO on the interaction between hERG and chaperones. A, C, E: Representative image of Western blot after immunoprecipitation; B: Statistical result of interaction between hERG and Hsp70; D, F: Statistical result of interaction between hERG and calnexin. n =3, $ \overline{x} $ ± SEM. *P < 0.05 vs Ctrl; #P < 0.05 vs THIO, figureFileSmall=X4+WNQ/PBg9GZz2pqiedqg==, figureFileBig=4QPDb7vmaUOlpkICAN2yhw==, tableContent=null), ArticleFig(id=1308817893782024684, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817728916517109, language=EN, label=null, caption=null, figureFileSmall=Jc5wHsUKEx5PSVIOy3DOZg==, figureFileBig=59JBB+qxyVGRLjVGeWVvBw==, tableContent=null), ArticleFig(id=1308817893870105069, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817728916517109, language=CN, label=Fig.6, caption=Effect of drugs on THIO-enhanced ICa, L currents. A: Protocol and examples for studying the ICa, L current under the conditions of THIO and TANIIA treatment; B: I-V curve of the ICa, L current. n = 11, $ \overline{x} $ ± SEM. *P < 0.05 vs Ctrl; #P < 0.05 vs THIO, figureFileSmall=Jc5wHsUKEx5PSVIOy3DOZg==, figureFileBig=59JBB+qxyVGRLjVGeWVvBw==, tableContent=null)], attaches=null, journal=Journal(id=1189982048455397383, delFlag=0, nameCn=药学学报, nameEn=Acta Pharmaceutica Sinica, nameHistory1=null, nameHistory2=null, issn=0513-4870, eissn=null, cn=11-2163/R, coden=null, periodic=0, language=CN, oaType=null, ccby=null, superviseOffice=null, ownerOffice=null, pubOffice=null, editorOffice=null, officeType=null, aims=null, clcCode=null, officeProv=null, officeCity=null, officeAddr=null, officeZip=null, officeEmail=null, officePhone=null, editDirector=null, officeDirector=null, officeDirectorPhone=null, officeStaffNum=null, officeEmpNum=null, coverPicUrl=BTxjudbJDVO4PqdBR6On6Q==, journalPrice=null, startedYear=null, abbrevIsoEn=null, 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应用hiPSC-CMs细胞模型比较不同药物对硫利达嗪诱发的acLQTS的逆转作用及机制
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李加欣 1 , 刘妍 1 , 李晓旭 1 , 洪海颖 1 , 周雨妍 1 , 宋莹 1 , 李宝馨 1, * , 樊攀 2, *
药学学报 | 研究论文 2026,61(2): 486-493
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药学学报 |研究论文 2026 , 61 (2) : 486 -493
应用hiPSC-CMs细胞模型比较不同药物对硫利达嗪诱发的acLQTS的逆转作用及机制
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李加欣1, 刘妍1, 李晓旭1, 洪海颖1, 周雨妍1, 宋莹1, 李宝馨1, * , 樊攀2, *
作者信息
  • 1哈尔滨医科大学药学院, 黑龙江 哈尔滨 150081
  • 2哈尔滨医科大学附属第二临床医学院, 黑龙江 哈尔滨 150081
通讯作者:
李宝馨, Tel: 86-451-86671354, E-mail:
樊攀, Tel: 86-451-86605704, E-mail:
作者简介:

#

共同第一作者.

作者贡献:

李加欣负责实验研究和文章撰写; 刘妍负责具体实验方案设计和实验指导; 李晓旭负责实验指导与研究; 洪海颖、周雨妍、宋莹负责实验研究; 樊攀负责图表制作、文章修改、审核及临床合作研究; 李宝馨负责课题设计、文章修改、审核及提供基金。

Application of hiPSC-CMs model to compare the reversal effects and mechanisms of different drugs on thioridazine-induced acLQTS
Jia-xin LI1, Yan LIU1, Xiao-xu LI1, Hai-ying HONG1, Yu-yan ZHOU1, Ying SONG1, Bao-xin LI1, * , Pan FAN2, *
Affiliations
  • 1College of Pharmacy, Harbin Medical University, Harbin 150081, China
  • 2The Second Affiliated Hospital, Harbin Medical University, Harbin 150081, China
出版时间: 2026-02-12 doi: 10.16438/j.0513-4870.2025-0746
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药物靶向心脏人类ether-à-go-go相关基因(human ether-à-go-go-related gene, hERG) 编码的快速延迟整流钾通道易诱发获得性长QT综合征(acquired long QT syndrome, acLQTS), 使患者发生危及生命的心律失常。抗精神失常药硫利达嗪(thioridazine, THIO) 在临床应用时产生诱发acLQTS的心脏毒性, 如何逆转并探索可能的机制即为本研究的目的。本研究应用人诱导多能干细胞衍生的心肌细胞(human induced pluripotent stem cell derived cardiomyocytes, hiPSC-CMs) 模型, 结合微电极阵列(multi-electrode array, MEA)、高分辨荧光标测技术评价比较了丹参酮ⅡA (tanshinone IIA, TANIIA)、普萘洛尔(propranolol, Prop)、白藜芦醇(resveratrol, Res) 对硫利达嗪引起的动作电位时程(action potential duration, APD)、场电位延长的逆转作用(所有动物实验均按照哈尔滨医科大学动物操作准则进行并得到哈尔滨医科大学伦理委员会的批准, 伦理号-IRB3020622)。结果显示, 丹参酮能够明显逆转硫利达嗪延长的APD90、APD50及场电位, 而普萘洛尔和白藜芦醇两药没有逆转硫利达嗪导致APD及场电位的延长作用。基于以上结果, 本研究进一步探索丹参酮ⅡA发挥逆转作用的机制及靶点。Western blot及全细胞膜片钳检测结果证实, 丹参酮ⅡA对硫利达嗪抑制的hERG蛋白具有明显的拯救作用, 其机制是丹参酮ⅡA通过减弱硫利达嗪造成的hERG蛋白与钙连蛋白(calnexin) 的相互作用, 拯救了硫利达嗪诱发的hERG通道蛋白折叠转运障碍, 同时hERG电流也增加; 此外丹参酮ⅡA明显减少了硫利达嗪所激活的钙电流。综上, 丹参酮ⅡA可以通过上调hERG蛋白、hERG电流及下调钙电流, 最终逆转硫利达嗪诱发的acLQTS, 有望成为临床上治疗acLQTS的有效药物。

硫利达嗪  /  丹参酮ⅡA  /  普萘洛尔  /  白藜芦醇  /  获得性长QT综合征  /  人诱导多能干细胞衍生的心肌细胞

Drug targeting of the human ether-à-go-go-related gene (hERG)-encoded rapid delayed rectifier potassium channel induces acquired long QT syndrome (acLQTS), predisposing individuals to life-threatening arrhythmias. Previous studies demonstrate that the antipsychotic agent thioridazine (THIO) triggers acLQTS. Our findings aimed to elucidate the underlying mechanisms of the therapeutic effects against drug-induced cardiotoxicity. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) integrated with multi-electrode arrays (MEA) and optical mapping technology, we evaluated and compared the efficacy of tanshinone IIA (TANIIA), propranolol (Prop) and resveratrol (Res) in reversing THIO-induced prolongation of action potential duration (APD) and field potential duration (all animal experiments were conducted in accordance with the Animal Care Guidelines of Harbin Medical University and were approved by the Ethics Committee of Harbin Medical University, the approval number is IRB3020622). The results showed that TANIIA significantly reversed the THIO-induced prolongation of APD90, APD50, and field potential, whereas neither Prop nor Res counteracted this effect. Building on these results, we further explored the mechanistic basis and molecular targets underlying TANIIA's reversal effects. Western blot and whole-cell patch-clamp demonstrated that TANIIA restored hERG protein expression downregulated by THIO and rescued its channel trafficking defects and rescued channel trafficking defects. Mechanistically, TANIIA attenuated THIO-induced aberrant interactions between hERG and the calnexin, thereby rectifying impaired channel folding and trafficking. Concurrently, TANIIA substantially reduced THIO-induced L-type calcium current. In conclusion, TANIIA ameliorates THIO-induced acLQTS by up regulating hERG current expression and down regulating L-type calcium current. These findings highlight its therapeutic potential of drug-induced acLQTS for clinical.

thioridazine  /  tanshinone IIA  /  propranolol  /  resveratrol  /  acquired long QT syndrome  /  human induced pluripotent stem cell-derived cardiomyocyte
李加欣, 刘妍, 李晓旭, 洪海颖, 周雨妍, 宋莹, 李宝馨, 樊攀. 应用hiPSC-CMs细胞模型比较不同药物对硫利达嗪诱发的acLQTS的逆转作用及机制. 药学学报, 2026 , 61 (2) : 486 -493 . DOI: 10.16438/j.0513-4870.2025-0746
Jia-xin LI, Yan LIU, Xiao-xu LI, Hai-ying HONG, Yu-yan ZHOU, Ying SONG, Bao-xin LI, Pan FAN. Application of hiPSC-CMs model to compare the reversal effects and mechanisms of different drugs on thioridazine-induced acLQTS[J]. Acta Pharmaceutica Sinica, 2026 , 61 (2) : 486 -493 . DOI: 10.16438/j.0513-4870.2025-0746
硫利达嗪是吩噻嗪类抗精神失常药物, 用于治疗精神分裂症和精神病, 目前也用于抗肿瘤的治疗[1], 尽管硫利达嗪临床前景可观, 但其引起的心脏毒性等不良反应同样引发关注, 在临床应用时患者出现长QT间期综合征及尖端扭转型室性心动过速甚至心脏骤停致死亡[2, 3], 此心脏毒性限制了该药的临床广泛应用。本课题组前期研究发现, 硫利达嗪可以诱发内质网应激反应致使hERG (human ether-à-go-go-related gene) 通道发生转运障碍, 未达到细胞膜就被降解, 从而导致hERG膜蛋白表达减少, 电流减少; 另一方面其增加细胞内钙离子浓度、激活L型钙通道, 是其诱发获得性长QT综合征(acquired long QT syndrome, acLQTS) 的主要原因[4], 寻找有效的药物进行干预将具有重要临床意义。
丹参酮ⅡA为一种天然抗氧化剂, 可治疗动脉粥样硬化、清除氧化的自由基。急性心肌梗死的发生常会伴随缺血性心律失常, 丹参酮ⅡA能降低氧化应激, 提高超氧化物歧化酶的活性, 对抗由缺血再灌注引起的心肌氧化损伤[5]。本课题组近期研究发现, 丹参酮ⅡA通过干预MALAT1/calpain-1信号通路, 逆转了三氧化二砷对hERG蛋白的抑制作用, 从而改善三氧化二砷所致的心脏毒性[6]。此外, 丹参酮ⅡA通过抑制钙离子通道来抑制血管增生过程[7], 并且具有L型钙通道阻断作用[8], 为与离子通道功能异常相关的心血管疾病治疗提供了更多的选择和可能性。
普萘洛尔是临床上常用的无内在拟交感活性的非选择性β受体阻滞剂, 通过阻断β-肾上腺素能受体, 减少心肌细胞的后除极, 从而有助于稳定心脏的电活动, 减少心律失常的发生[9]。普萘洛尔可能不仅通过阻滞β受体缩短QT间期[10], 还可能对钠通道及L型钙通道有阻断作用[11]。白藜芦醇是一种天然多酚化合物, 其又称芪三酚, 在抗氧化、抗心血管疾病和抗肿瘤等方面具有一定的治疗效果。在缺氧条件下, 活性氧(ROS) 和Ca2+的稳态发生变化, 白藜芦醇能够减少缺氧诱导的ROS生成和升高细胞内Ca2+浓度[12]。
药物诱发的acLQTS与药物抑制心肌细胞膜上的延迟整流钾通道Ikr、促进L型钙通道以及影响钠通道等有关[13], 其中90%以上是药物抑制Ikr/hERG通道导致[14]。hERG基因编码快速激活延迟整流钾通道Ikr的α亚基[15], Ikr是复极过程中主要的钾电流, 决定动作电位时程(action potential duration, APD)。因此本文主要以hERG通道和L型钙通道作为靶点, 评价所选3种药物是否可以拯救硫利达嗪诱发的心脏毒性。
药品与试剂  抗体hERG (货号: sc-377388)、热休克蛋白70 (heat shock protein 70, Hsp70) (货号: sc-59569)、calnexin (货号: sc-46669) 均购自Santa Cruz Biotechnology公司; 山羊抗兔IgG (货号: 926-32211)、山羊抗鼠IgG (货号: 926-32210) 均购自美国Li-CoR Biosciences公司; β-actin (货号: 66009-1-lg) 购自武汉三鹰shengwu技术有限公司; 胎牛血清(FBS) 购自美国Gibco公司; DMEM高糖培养基购自美国Hyclone公司; 青霉素-链霉素溶液(货号: C0222)、细胞裂解液(货号: P0013)、胰蛋白酶(C0201)、SDS-PAGE蛋白上样缓冲液(5×) (货号: P0015) 购自碧云天生物技术公司; 细胞级PBS缓冲液(货号: BL345A)、肝素(货号: BL1370A) 购自白鲨生物; G418 (货号: G274348) 购自上海阿拉丁生化科技股份有限公司; 硫利达嗪购自哈尔滨医大药业; 丹参酮ⅡA (货号: Y0001560)、普萘洛尔(货号: 00881-25MG)、白藜芦醇(货号: Y0001194)、NaCl (货号: S5886)、KCl (货号: P5405)、HEPES (货号: H4034)、MgCl2·6H2O (货号: PHR2486)、CaCl2 (货号: C4901)、葡萄糖(货号: D9434)、NaOH (货号: 415413)、Mg-ATP (货号: A9187)、乙二醇双(2-氨基乙基醚)四乙酸(货号: 324628)、GTP (货号: 10106399001)、KOH (货号: 757551)、Tris-Cl (货号: T5941)、CsCl (货号: 289329)、CsOH (货号: 516988)、天门冬氨酸(货号: A6558) 均购自美国Sigma公司; GS967 (货号: HY-12593) 购自美国MCE公司; 人多潜能干细胞复苏培养基、人心肌细胞纯化培养基、人心肌细胞维持培养基、人心肌细胞接种培养基购自北京赛贝生物技术有限公司; RH237 (货号: S1109) 购自美国Thermo Fisher公司; Blebbistatin (货号: S7099) 购自SelleckChem公司。
实验动物  SPF级豚鼠(雄性, 200 ± 20 g) 购于辽宁长生生物科技有限公司[实验动物合格证号: SCXK (辽) 2020-0001], 在室温23 ± 2 ℃、湿度55% ± 5%的标准动物室内饲养。每天给予适量高压灭菌纯净水和普通维持饲料, 12 h交替光照。本实验涉及的所有动物实验均按照哈尔滨医科大学动物操作准则进行并得到哈尔滨医科大学伦理委员会的批准, 伦理号-IRB3020622。
细胞  稳定转染hERG基因的HEK293细胞系(hERG-HEK293) 和HEK293细胞系获赠于哈尔滨医科大学药学院王志国教授; 人多潜能干细胞诱导分化的心肌细胞(hiPSC-CMs) 购买于北京赛贝生物技术有限公司。
Western blot检测蛋白表达  加药24 h后的细胞置于冰上, 弃培养液, 用Western及IP细胞裂解液提取蛋白超声离心后用NanoDrop 2000c (美国Thermo公司) 分光光度计测定蛋白浓度, 保证上样质量一致。100 ℃金属浴(大龙兴创实验仪器有限公司) 加热8 min使蛋白变性后进行SDS-PAGE凝胶电泳(美国BIO-RAD公司)。恒压70 V电泳30 min后, 调整至恒压110 V, 直至蛋白条带到达凝胶底部结束电泳。根据1 min转印1 kDa时间确定检测蛋白的转膜时间。转膜后将NC放入对应的一抗及稀释液中于4 ℃摇床(江苏金城国盛实验仪器厂) 过夜孵育。第二天, PBST清洗NC膜, 每次10 min, 共3次。清洗后根据一抗种属避光孵育二抗1 h, 孵育后PBST清洗NC膜, 每次10 min, 共3次。最后使用Odyssey荧光扫描系统(美国LI-COR公司) 检测, Image Studio进行分析得到目的条带。
蛋白质免疫共沉淀法提取蛋白  加药24 h后的细胞置于冰上, 弃培养液, 加入裂解液, 提取蛋白裂解30 min后离心, 用NanoDrop 2000c分光光度计测定蛋白的浓度, 使总质量和体积均相等。一抗4 ℃过夜。次日加入磁珠, 4 ℃过夜。加入预冷PBST后, 洗涤磁珠, 离心弃上清液, 反复操作3或4次后加入蛋白上样缓冲液, 涡旋混匀。100 ℃金属浴加热8 min, 制备样品。
膜片钳记录
试剂配制方法  ①电极外液(IhERG, mmol·L) 组成: NaCl 136, KCl 5.4, HEPES 5, MgCl2·6H2O 1, CaCl2 1, 葡萄糖10; 使用NaOH溶液将pH调节至7.4。②电极内液(IhERG, mmol·L) 组成: KCl 130, MgCl2·6H₂O 1, HEPES 10, Mg-ATP 5, EGTA 5, GTP 0.1; 使用KOH溶液将pH调节至7.3。③电极外液(ICa, L, mmol·L) 组成: Tris-Cl 136, CsCl 5.4, CaCl2 2, MgCl2 1, HEPES 10, 葡萄糖5; 使用Tris-OH溶液将pH调节至7.4。④电极内液(ICa, L, mmol·L) 组成: CsCl 20, CsOH 110, Mg-ATP 5, MgCl2 1, HEPES 10, EGTA 5, GS967 0.002 1, 天门冬氨酸110; 使用CsOH溶液将pH调节至7.3。
记录hERG电流的hERG细胞处理将细胞从孵箱(美国Thermo公司) 中取出, 胰酶消化液消化细胞, 在显微镜下观察细胞几乎全部呈单个悬浮状即可。终止消化离心重悬细胞。滴入1至2滴hERG细胞悬液于浴槽hERG外液中, 静置, 即可进行下步操作。
记录L型钙电流(ICa, L) 的原代乳鼠心肌细胞处理将细胞爬片从孵箱中取出, 放入浴槽中的电极外液中, 即可进行下步操作。
室温下, 使用垂直电极拉制仪(日本Narishige公司), 于70.0和52.0 ℃下制备玻璃电极, 将拉制好的玻璃电极充入电极内液后插入固定在膜片钳(美国Ason Instrument公司) 微操探头上, 要求灌注电极内液后阻值控制在2~4 MΩ内。在目镜视野下寻找单个、相对较大、表面光滑的细胞, 下调电极使其电极接触到细胞膜表面, 给予负压吸引使细胞与电极尖端形成高阻封接(阻值> 1 GΩ), 用脉冲或抽吸的方法打破细胞膜, 便形成全细胞记录模式, 补偿串连电阻和电容电流后, 便可在电压钳模式下进行刺激和记录。根据规定的刺激程序记录电压膜片钳模式下的hERG电流或L型钙电流, 保存记录的电流数据, 进行后续的数据处理分析。
电压敏感染料膜电位光学标测  开启系统阀门, 灌注台式液排出心脏中多余的血, 调节阀门以4~6 mL·min-1的速度提供动脉压。在体系中的台式液中加入blebbistatin使心脏停止跳动, 尽可能抑制心脏运动伪影。心脏停止跳动后, 关灯避光, RH237染料进行染色。使用单色发光装置在710 nm激发染料。将电极正负极与心尖接触, 使用PowerLab 26T刺激仪释放心脏起搏信号(5、6.7、8、10 Hz)。调节显微镜粗准焦使视野变清晰, Optical mapping成像系统(日本Brainvision公司) 以每秒2 000帧获取图像。滤波器设为1 kHz。
多电极阵列谱条件  该实验由北京赛贝生物技术有限公司检测。前一天用心肌细胞铺底工作液对电极板进行铺底, 每孔5 μL, 37 ℃过夜。37 ℃解冻细胞, 快速摇晃使细胞融化至仅剩一小块冰晶(避免冻存管盖接触水面), 迅速取出并用75%酒精消毒冻存管外表面, 转移至无菌操作台中。用1 mL移液器小心将细胞悬液转移至一个新的15 mL离心管, 避免反复剧烈吹吸。用1 mL人心肌细胞维持培养基润洗冻存管, 以收集剩余细胞。然后逐滴加入含有细胞悬液的15 mL离心管, 由于滴加的稀释比例较大, 应维持在5 s 1滴(50 μL) 的较慢速率, 滴加过程中不断轻摇混匀。滴加的速率不变, 仍5 s 1滴, 再依次逐滴加入4 mL人心肌细胞维持培养基, 滴加过程中不断轻摇混匀。200 ×g离心5 min吸弃上清液, 加入适量培养液, 进行细胞计数, 并按照4×104个/孔对培养液体积进行调整, 调整每毫升细胞数为8×106个。将心肌细胞接种到电极板, 接种每孔前, 吸去孔中预先铺好的心肌细胞铺底工作液, 并取5 μL细胞悬液小心接种到电极板上, 注意接种前将细胞悬液吹匀。全部接种结束后, 将电极板放入细胞培养箱, 4~6 h后取出观察, 此时细胞已经开始贴壁, 向每孔补充心肌细胞培养液300 μL, 放入细胞培养箱中培养, 2~3天换液一次。接种细胞7天后, 用仪器检测心肌细胞的电信号。分别加入硫利达嗪、硫利达嗪+普萘洛尔、硫利达嗪+丹参酮ⅡA、硫利达嗪+白藜芦醇几种药, 24 h后观察细胞停止跳动, 换液撤掉药, 细胞恢复跳动后, 用MEA微电极阵列采集系统[蔼可芯昂生物仪器(上海) 有限公司] 检测心肌细胞电信号, 并分析数据。
统计学分析  数据以平均数±标准误(SEM) 表示。数据分析采用GraphPad Prism5.0。两组数据比较的统计分析方法student's t-test; 多组数据比较的统计分析方法: Turkey's test或单因素方差。当P < 0.05认为有统计学意义。
硫利达嗪抑制hERG电流、激活L型钙通道, 最终延长APD。本研究在体水平上探究3种药物是否对硫利达嗪延长的APD具有逆转作用。首先将25只雄性豚鼠分为对照组、硫利达嗪(25 mg·kg-1) 组、硫利达嗪(25 mg·kg-1) + 丹参酮ⅡA (5 mg·kg-1) 组、硫利达嗪(25 mg·kg-1) + 普萘洛尔(10 mg·kg-1) 组、硫利达嗪(25 mg·kg-1) + 白藜芦醇(90 mg·kg-1) 组, 采用电压敏感染料膜电位光学标测技术对豚鼠心脏进行实验, 分别以5.0、6.7、8.0、10.0 Hz进行刺激起搏。结果显示, 在200 ms时硫利达嗪明显延长豚鼠心脏的APD90和APD50, 3个药物具有一定的逆转作用, 其中只有丹参酮ⅡA明显缩短APD90和APD50。200 ms时, 对照组豚鼠心脏的APD90和APD50分别为80.00 ± 1.40 ms和25.27 ± 3.05 ms, 灌胃7日后硫利达嗪组APD90和APD50延长至110.27 ± 1.94 ms和60.80 ± 3.72 ms, 丹参酮ⅡA组APD90和APD50分别缩短至87.47 ± 5.13和40.48 ± 1.99 ms (图1)。
综合体外致心律失常评价(CiPA) 和日本心脏安全性评估(JiCSA) 等已经证明hiPSC-CMs/MEA可用于评估候选药物的致逆转性潜能。本研究使用该细胞模型应用多电极阵列技术比较药物对于hiPSC-CMs细胞场电位的影响, 结果发现, 丹参酮ⅡA逆转了硫利达嗪引起的场电位持续时间延长(P < 0.05); 其他两组无统计学意义(图2)。
实验证明以上3种逆转药物中, 丹参酮ⅡA可以拯救硫利达嗪导致的动作电位及场电位的延长, 因此本文继续探究了丹参酮ⅡA对硫利达嗪引起的acLQTS机制。分别用3 μmol·L-1硫利达嗪、3 μmol·L-1硫利达嗪+ 10 μmol·L-1丹参酮ⅡA、3 μmol·L-1硫利达嗪+ 30 μmol·L-1丹参酮ⅡA作用于hERG-HEK293细胞孵育给药24 h, 通过Western blot方法检测成熟(155 kDa) hERG蛋白的表达情况(图3)。结果显示3 μmol·L-1硫利达嗪作用后使成熟的155 kDa hERG蛋白水平显著降低, 当3 μmol·L-1硫利达嗪+ 10 μmol·L-1丹参酮ⅡA作用后拯救了hERG蛋白的部分表达, 拯救率为44.75% ± 8.90% (P < 0.05)。当3 μmol·L-1硫利达嗪+ 30 μmol·L-1丹参酮ⅡA作用后对hERG蛋白的表达无明显拯救作用, 这也说明丹参酮ⅡA对hERG蛋白的拯救不具备浓度依赖性。
为了进一步验证丹参酮ⅡA拯救的hERG蛋白是否为具有功能性的通道蛋白, 利用全细胞膜片钳记录hERG-HEK293细胞在药物孵育24 h后对hERG通道电流的影响, 由于10 μmol·L-1丹参酮ⅡA对hERG蛋白具有较强的拯救作用, 将细胞分为对照组、硫利达嗪(3 μmol·L-1) 组、硫利达嗪+ 丹参酮ⅡA (10 μmol·L-1) 组, 孵育24 h后记录hERG电流。结果如图4所示, 在+40 mV时, 硫利达嗪单孵育hERG电流密度较对照组降低, 两药共孵育下的hERG电流密度较硫利达嗪组升高。结果说明, 丹参酮ⅡA可以拯救硫利达嗪抑制的hERG电流, 也证实其拯救的蛋白为功能性的hERG通道蛋白。
硫利达嗪破坏hERG与Hsp70的相互作用来干扰hERG通道的正确折叠转运过程, 致通道蛋白无序降解, 同时硫利达嗪上调内质网标志性蛋白ATF6蛋白、激活下游靶蛋白calnexin等, 最终诱发内质网应激反应。
为了探究丹参酮ⅡA是否通过影响hERG与伴侣蛋白Hsp70、calnexin的相互作用, 拯救硫利达嗪引起的hERG蛋白表达, 本研究进行了免疫共沉淀实验验证(图5), 将hERG-HEK293细胞分为对照组、硫利达嗪(3 μmol·L-1) 组、硫利达嗪+ 丹参酮ⅡA (10 μmol·L-1) 组, 孵育24 h后提取细胞总蛋白, 分别用hERG、Hsp70和calnexin的一抗沉淀对应的蛋白后, 与对照组相比, 硫利达嗪组的hERG与Hsp70相互作用明显降低。但与硫利达嗪组相比, 丹参酮ⅡA没有逆转hERG-Hsp70的相互作用, 不具有统计学意义。与对照组相比, 硫利达嗪组的hERG与calnexin相互作用明显增强。与硫利达嗪组相比, 丹参酮ⅡA降低硫利达嗪引起hERG-calnexin的相互增强作用(P < 0.05)。
硫利达嗪除了可以通过降低hERG膜蛋白来延长动作电位, 研究发现硫利达嗪还可以上调氧化性钙调蛋白激酶活性, 从而激活L型钙通道, 为了进一步探究拯救药物对硫利达嗪引起的钙电流增大的影响, 采用全细胞膜片钳技术记录对照组、硫利达嗪(3 μmol·L-1) 组、硫利达嗪+ 丹参酮ⅡA (10 μmol·L-1) 孵育24 h后原代乳鼠心肌细胞的L型钙电流。结果如图6所示, 丹参酮ⅡA逆转硫利达嗪致钙电流升高。
硫利达嗪为抗精神失常类药物, 目前也用于抗肿瘤的治疗, 但其严重的心脏毒性尤其是引发的acLQTS引起人们的关注。LQTS一种恶性心肌离子通道疾病, 容易诱发尖端扭转型室性心动过速, 严重时会发生心源性猝死。因此, 寻找有效的治疗遗传性LQTS药物或拯救药物诱发的acLQTS的药物, 并探究其机制成为本课题的主要研究目标。
目前研究表明, 药物诱发的acLQTS主要机制是药物抑制了心肌细胞的hERG通道, 包括瞬时阻断hERG电流或降低细胞膜上通道蛋白表达水平。同时由于钙电流参与动作电位2相平台期, 药物通过激动心肌细胞钙电流也会延长QT间期。
hiPSC-CMs细胞模型是心脏安全性评价的重要模型之一, 相比于其他传统的动物及单细胞系模型, 其具有与人类心肌细胞高度相似的离子通道、模拟人类心肌细胞的电生理和收缩特性, 为药物毒性研究提供更为准确的预测, hiPSC-CMs模型已成为当今临床前心脏安全性评价的公认模型[16]。
普萘洛尔是非选择性β受体阻断剂, 是治疗LQTS主要药物之一; 丹参酮ⅡA、白藜芦醇都具有良好的抗氧化作用及心血管系统的保护作用, 两者可能通过显著的抗氧化能力抑制活性氧的过量产生而逆转作用。因此, 本研究在hiPSC-CMs细胞模型上评价以上3种具有拯救潜能的药物对硫利达嗪诱发的acLQTS的治疗效果。
因hiPSC-CMs和豚鼠在体心脏模型能综合模拟人类心脏的多离子通道电生理活动, 所以其模型广泛用于评估药物的致心律失常潜力。虽然临床研究表明普萘洛尔和白藜芦醇可以缩短QT间期, 但本课题组前期研究显示, 二者均未能逆转硫利达嗪在上述两种模型中引起的动作电位延长。值得注意的是, 普萘洛尔的作用机制涉及逆转硫利达嗪干扰的内质网应激反应, 通过恢复hERG与Hsp70及calnexin的正常相互作用, 从而修复功能性hERG膜蛋白表达。但是这一机制可能不足以对抗硫利达嗪在复杂体系中引发的整体心脏毒性。然而经本研究证实, 丹参酮ⅡA可显著降低硫利达嗪引起的豚鼠心脏及hiPSC-CMs动作电位延长, 因此本文着重继续研究丹参酮ⅡA逆转硫利达嗪的心脏毒性机制。
前期的研究发现, 丹参酮ⅡA能促进hERG蛋白表达, 且逆转了三氧化二砷引起的hERG蛋白的抑制作用[5], 故本研究应用稳定表达hERG通道的hERG-HEK293细胞系, 验证丹参酮ⅡA能否靶向hERG通道发挥逆转硫利达嗪的作用。结果显示, 丹参酮ⅡA明显逆转了硫利达嗪抑制的hERG蛋白, 但增加丹参酮ⅡA浓度却不产生更强的效果, 可能原因是, 当丹参酮ⅡA浓度增加时, 对细胞活力会产生影响, 其对蛋白质的表达也会产生不良影响。
本研究设计实验进一步证实丹参酮ⅡA促进hERG蛋白表达的分子机制, 前期研究发现硫利达嗪引起内质网应激, 进而促进hERG蛋白的降解[4], 即硫利达嗪促进了内质网应激标志蛋白ATF-6蛋白的表达, 导致下游的calnexin蛋白表达增加。Calnexin蛋白是一种位于内质网的伴侣蛋白, 协助糖蛋白进行正确折叠和修饰。Calnexin也可以识别并结合折叠不完全或错误的蛋白, 协助其重新折叠。如仍无法正确折叠, calnexin会通过内质网相关降解系统, 逆向转运至细胞质, 经泛素-蛋白酶体途径进行降解。因此, 本实验观察了丹参酮ⅡA是否通过影响hERG与calnexin蛋白的相互作用, 进而逆转硫利达嗪引起的hERG蛋白表达减少, 结果显示丹参酮ⅡA逆转了硫利达嗪引起的hERG与calnexin蛋白的相互作用, 减轻hERG通道蛋白在内质网中的错误折叠转运障碍, 促使膜蛋白表达增加。
此外, 丹参酮ⅡA通过减少硫利达嗪所致心肌细胞内活性氧水平的增高, 使得激活后的氧化型钙调蛋白激酶与L型钙通道α亚基结合下调, 从而升高L型钙通道的失活速度, 降低其开放频率, 降低其开放时间, 逆转硫利达嗪引起的L型钙电流的升高。
丹参酮ⅡA已在多项随机对照试验中用于治疗不稳定心绞痛、心肌梗死、高血压肾病、动脉粥样硬化以降低心肌肌钙蛋白-Ⅰ (cTn-Ⅰ)、高敏C反应蛋白(hs-CRP) 改善血管弹性、降低血压、减少不良心血管事件。并且可通过纳米粒、脂质体等剂型提高递送效率, 改善丹参酮ⅡA的低口服生物利用度。
综上, 丹参酮ⅡA通过影响hERG与calnexin蛋白相互作用逆转细胞膜上hERG蛋白的表达, 进而增加hERG电流及下调L型钙电流, 拯救硫利达嗪诱发的APD及QT间期的延长, 该药有望成为临床治疗药物诱发acLQTS的有效药物。

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2026年第61卷第2期
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doi: 10.16438/j.0513-4870.2025-0746
  • 接收时间:2025-06-30
  • 首发时间:2026-09-21
  • 出版时间:2026-02-12
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  • 收稿日期:2025-06-30
  • 修回日期:2025-11-09
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    1哈尔滨医科大学药学院, 黑龙江 哈尔滨 150081
    2哈尔滨医科大学附属第二临床医学院, 黑龙江 哈尔滨 150081

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小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
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