Berberine attenuates sunitinib-induced cardiac dysfunction by normalizing calcium regulation disorder via SGK1 activation. (May 2023)

• Record Type: Journal Article
• Authors: Li, Congxin; Wu, Wenting; Xing, Jiahui; Yan, Wei; Zhang, Jiali; Sun, Jinglei; Zhang, Zhihan; Qiu, Suhua; Xu, Yanfang; Wang, Xianying
• Is Part Of: Food and chemical toxicology. Volume 175(2023)
• Publication Date: 2023-05
• Subjects: Berberine -- Sunitinib -- Cardiac contractile dysfunction -- Phosphoinositide 3-kinase -- Serum and glucocorticoid-regulated kinase 1 -- Human-induced pluripotent stem cell-derived cardiomyocyte; AMPK AMP-activated protein kinase -- BBR Berberine -- CICR Calcium-induced calcium release -- H&E Hematoxylin and eosin -- hiPSC-CMs human induced pluripotent stem cell-derived cardiomyocytes -- LVEF Left ventricular ejection fraction -- LVFS Left ventricular fractional shortening -- NCX Na+/Ca2+ exchange -- NRVM Neonatal rat ventricular myocytes -- PI3K phosphoinositide 3-kinase -- SNT Sunitinib -- SGK1 Serum and glucocorticoid-regulated kinase 1 -- TKI Tyrosine kinase inhibitor; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2023.113743
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: 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 2+ 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. Graphical abstract: Image 1 Highlights: Sunitinib (SNT) causes left ventricular systolic dysfunction. SNT inhibition of SGK1 activity is an important cause of cardiotoxicity. Berberine activates PI3K-SGK1 activity to inhibit cardiotoxicity. Berberine normalizes calcium regulation disorder via SGK1 activation.