Li Congxin, Wu Wenting, Xing Jiahui, Yan Wei, Zhang Jiali, Sun Jinglei, Zhang Zhihan, Qiu Suhua, Xu Yanfang, Wang Xianying
Department of Pharmacy, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China.
Department of Pharmacology, Hebei Medical University, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, 050017, China.
Food Chem Toxicol. 2023 May;175:113743. doi: 10.1016/j.fct.2023.113743. Epub 2023 Mar 26.
Sunitinib (SNT)-induced cardiotoxicity is associated with abnormal calcium regulation caused by phosphoinositide 3 kinase inhibition in the heart. Berberine (BBR) is a natural compound that exhibits cardioprotective effects and regulates calcium homeostasis. We hypothesized that BBR ameliorates SNT-induced cardiotoxicity by normalizing the calcium regulation disorder via serum and glucocorticoid-regulated kinase 1 (SGK1) activation. Mice, neonatal rat cardiomyocytes (NRVMs), and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were used to study the effects of BBR-mediated SGK1 activity on the calcium regulation disorder caused by SNT as well as the underlying mechanism. BBR offered prevention against SNT-induced cardiac systolic dysfunction, QT interval prolongation, and histopathological changes in mice. After the oral administration of SNT, the Ca transient and contraction of cardiomyocytes was significantly inhibited, whereas BBR exhibited an antagonistic effect. In NRVMs, BBR was significantly preventive against the SNT-induced reduction of calcium transient amplitude, prolongation of calcium transient recovery, and decrease in SERCA2a protein expression; however, SGK1 inhibitors resisted the preventive effects of BBR. In hiPSC-CMs, BBR pretreatment significantly prevented SNT from inhibiting the contraction, whereas coincubation with SGK1 inhibitors antagonized the effects of BBR. These findings indicate that BBR attenuates SNT-induced cardiac dysfunction by normalizing the calcium regulation disorder via SGK1 activation.
舒尼替尼（SNT）诱导的心脏毒性与心脏中磷酸肌醇3激酶抑制导致的钙调节异常有关。黄连素（BBR）是一种具有心脏保护作用并调节钙稳态的天然化合物。我们假设BBR通过激活血清和糖皮质激素调节激酶1（SGK1）使钙调节紊乱正常化，从而改善SNT诱导的心脏毒性。使用小鼠、新生大鼠心肌细胞（NRVMs）和人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）来研究BBR介导的SGK1活性对SNT引起的钙调节紊乱的影响及其潜在机制。BBR可预防SNT诱导的小鼠心脏收缩功能障碍、QT间期延长和组织病理学变化。口服SNT后，心肌细胞的钙瞬变和收缩受到显著抑制，而BBR表现出拮抗作用。在NRVMs中，BBR可显著预防SNT诱导的钙瞬变幅度降低、钙瞬变恢复延长和SERCA2a蛋白表达减少；然而，SGK1抑制剂可抵抗BBR的预防作用。在hiPSC-CMs中，BBR预处理可显著预防SNT抑制收缩，而与SGK1抑制剂共同孵育可拮抗BBR的作用。这些发现表明，BBR通过激活SGK1使钙调节紊乱正常化，从而减轻SNT诱导的心脏功能障碍。
