小檗碱激活SGK1保护舒尼替尼导致心肌损伤  

Berberine Activates SGK1 to Protect Myocardial Iinjury Induced by Sunitinib

作　　者：李从欣 李雪靖[1] 郄素会[1] 阎伟[1] 高媛 LI Congxin;LI Xuejing;QIE Suhui;YAN Wei;GAO Yuan(Dept.of Pharmacy,Hebei Medical University Third Hospital,Shijiazhuang 050051,China)

机构地区：[1]河北医科大学第三医院药剂科,石家庄050051

出　　处：《世界科学技术-中医药现代化》2025年第2期384-390,共7页Modernization of Traditional Chinese Medicine and Materia Medica-World Science and Technology

基　　金：国家自然科学基金资助项目(82003878):酪氨酸激酶抑制剂扰动PI3K-SGK1通路致心脏收缩功能障的分子机制研究,负责人:李从欣;河北省自然科学基金面上项目(H2024206062):PKCε调控IP3R1/GRP75/VDAC1复合体介导线粒体钙超载致舒尼替尼心脏毒性的机制研究,负责人:李从欣;河北省卫健委医学研究指令性课题(20240157):抗肿瘤药物舒尼替尼的心脏毒性及风险标志物研究,负责人:高媛。

摘　　要：目的在人诱导多功能干细胞衍生心肌细胞(hiPSC-CMs)和新生大鼠心肌细胞(NRVMs)水平,观察血清糖皮质激素调节激酶1(SGK1)在舒尼替尼导致心肌损伤中的作用及小檗碱潜在其中的保护作用。方法采用酶联免疫吸附法检测舒尼替尼及小檗碱给药对hiPSC-CMs人氨基端前脑钠素(NTproBNP)和心肌肌钙蛋白I(cTn-I)水平的影响;采用激酶活性光度法定量检测舒尼替尼及小檗碱给药对hiPSC-CMs SGK1活性的影响;免疫印迹(Western blot)检测NRVMs中SGK1的表达情况;并应用SGK1阻断剂进行SGK1阻断后检测上述指标。结果舒尼替尼和SGK1抑制剂显著升高了hiPSC-CMs的NT-proBNP水平(P<0.01),小檗碱给药激活SGK1可以显著降低NT-proBNP和cTn-I水平(P<0.01),SGK1抑制剂给药抵抗小檗碱的保护作用(P<0.01)。舒尼替尼和SGK1抑制剂显著降低hiPSC-CMs SGK1活性(P<0.01),小檗碱给药激活SGK1可以显著保护舒尼替尼导致的hiPSC-CMs SGK1活性抑制(P<0.01)。舒尼替尼和SGK1抑制剂显著降低NRVMs中SGK1蛋白表达(P<0.01),小檗碱给药激活SGK1可以显著保护舒尼替尼导致的SGK1蛋白表达下调(P<0.01)。结论舒尼替尼抑制SGK1活性导致心肌损伤,小檗碱激活SGK1具有保护作用。Objective At the level of human induced pluripotent stem cell-derived cardiomyocytes(hi PSC-CMs)and neonatal rat cardiomyocytes(NRVMs),investigate the role of serum glucocorticoid regulated kinase 1(SGK1)in the myocardial injury caused by sunitinib and the potential protective effect of berberine.Methods Enzyme-linked immunosorbent assay was used to detect the effect of sunitinib and incubation with berberine on the level of NT-pro BNP and cTn-I in hi PSC-CMs.The effect of sunitinib and incubation with berberine on the activity of SGK1 in hi PSC-CMs was quantitatively tested using kinase activity photometry.Western blot was used to detect the expression of SGK1 in NRVMs.And the above indicators were detected again after SGK1 blockade using SGK1 blocker.Results Sunitinib and SGK1 inhibitor significantly increased the NT-pro BNP and cTn-I level of hi PSC-CMs(P<0.01),and incubation with berberine activated SGK1 could significantly protect hi PSC-CMs from the increase inNT-pro BNP level caused by sunitinib(P<0.01),while the SGK1 inhibitor resisted the protective effect of berberine(P<0.01).Sunitinib and SGK1 inhibitor significantly decreased the activity of SGK1 in hi PSC-CMs(P<0.01),and incubation with berberine activated SGK1,which significantly protected hi PSC-CMs from the inhibition of SGK1 activity caused by sunitinib(P<0.01).Sunitinib and SGK1 inhibitors significantly reduced SGK1 protein expression in NRVMs(P<0.01),and incubating berberine to activate SGK1 significantly protected SGK1 protein expression decrease induced by sunitinib(P<0.01).Conclusions Sunitinib inhibits the activity of SGK1,leading to myocardial injury,while berberine activates SGK1 and has protective effects.

关 键 词：舒尼替尼 心肌损伤 人诱导多功能干细胞衍生心肌细胞 新生大鼠心肌细胞 小檗碱 血清糖皮质激素调节激酶1 

分 类 号：R96[医药卫生—药理学]