Role of PI3K in systolic dysfunction of hiPSC-CMs induced by sunitinib
- VernacularTitle:PI3K在舒尼替尼致hiPSC-CMs收缩功能障碍中的作用
- Author:
Congxin LI
1
;
Guoqiang LIU
1
;
Yang LIU
1
;
Zhihan ZHANG
2
;
Wei YAN
1
;
Chunhui LIANG
1
Author Information
1. Dept. of Pharmacy,the Third Hospital of Hebei Medical University,Shijiazhuang 050051,China
2. Dept. of Clinical Nutrition,the Fourth Hospital of Hebei Medical University,Shijiazhuang 050011,China
- Publication Type:Journal Article
- Keywords:
sunitinib;
systolic dysfunction;
cardiotoxicity;
phosphatidylinositol-3-kinase;
human induced pluripotent stem cell-
- From:
China Pharmacy
2023;34(2):139-143
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE To study the role of phosphatidylinositol-3-kinase (PI3K) on sunitinib-induced myocardial systolic dysfunction. METHODS Using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMS) as objects, the contractile force of cardiomyocytes was measured by CardioExcyte 96 system, and IC50 of sunitinib was calculated after hiPSC- CMS were treated with sunitinib at different concentrations [0 (control), 0.5, 1, 3, 5, 10 μmol/L] for 24 hours. The effects of sunitinib (3.14 μmol/L) on the contractile frequency of cardiomyocytes, calcium transient amplitude and calcium transient recovery time course, mRNA expression of myocardial injury markers atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC) were detected. PI3K activator 3,4,5-triphosphate phos-phatidylinositol (PIP3, 1 μmol/L) and sunitinib were used to intervene in hiPSC-CMs jointly, so as to investigate the role of PI3K in the myocardial systolic dysfunction induced by sunitinib. RESULTS Sunitinib inhibited the contractile force of hiPSC-CMs in a concentration-dependent manner. IC50 of sunitinib was 3.14 μmol/L. After intervention with 3.14 μmol/L sunitinib, the contractile frequency of hiPSC-CMs and calcium transient amplitude were decreased significantly (P<0.05 or P<0.01); the duration of calcium transient recovery was prolonged significantly (P<0.05), and mRNA expressions of ANP, BNP and β-MHC were significantly increased (P<0.01). After PI3K was activated with PIP3, the contractile force of hiPSC-CMs was increased significantly (P<0.01). CONCLUSIONS Activating PI3K activity is a potential molecular mechanism to improve myocardial toxicity induced by sunitinib.