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.
