Role of PI3K in systolic dysfunction of hiPSC-CMs induced by sunitinib

LI Congxin; LIU Guoqiang; LIU Yang; ZHANG Zhihan; YAN Wei; LIANG Chunhui

doi:10.6039/j.issn.1001-0408.2023.02.03

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Role of PI3K in systolic dysfunction of hiPSC-CMs induced by sunitinib

更新时间：2023-02-22

- Role of PI3K in systolic dysfunction of hiPSC-CMs induced by sunitinib
- ZHONGGUO YAOFANG Vol. 34, Issue 2, Pages: 139-143(2023)
- 作者机构：
  
  1.河北医科大学第三医院药剂科，石家庄　050051
  2.河北医科大学第四医院临床营养科，石家庄　050011
- 作者简介：
- 基金信息：
- DOI：10.6039/j.issn.1001-0408.2023.02.03
  CLC： R965
- Published：30 January 2023，
  
  Received：08 July 2022，
  
  Revised：15 December 2022，
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李从欣,刘国强,刘洋等.PI3K在舒尼替尼致hiPSC-CMs收缩功能障碍中的作用 ^Δ[J].中国药房,2023,34(02):139-143.

LI Congxin,LIU Guoqiang,LIU Yang,et al.Role of PI3K in systolic dysfunction of hiPSC-CMs induced by sunitinib[J].ZHONGGUO YAOFANG,2023,34(02):139-143.
李从欣,刘国强,刘洋等.PI3K在舒尼替尼致hiPSC-CMs收缩功能障碍中的作用 ^Δ[J].中国药房,2023,34(02):139-143. DOI： 10.6039/j.issn.1001-0408.2023.02.03.

LI Congxin,LIU Guoqiang,LIU Yang,et al.Role of PI3K in systolic dysfunction of hiPSC-CMs induced by sunitinib[J].ZHONGGUO YAOFANG,2023,34(02):139-143. DOI： 10.6039/j.issn.1001-0408.2023.02.03.

摘要

目的

研究磷脂酰肌醇-3-激酶（PI3K）在舒尼替尼致心肌收缩功能障碍中的作用。

方法

以人源诱导型多能干细胞来源的心肌细胞（hiPSC-CMs）为研究对象，以不同浓度[0（对照）、0.5、1、3、5、10 μmol/L]舒尼替尼干预hiPSC-CMs 24 h后，采用CardioExcyte 96系统检测细胞收缩力，并计算半数抑制浓度（IC

）；检测舒尼替尼（3.14 μmol/L）对细胞收缩频率、钙瞬变幅度、钙瞬变恢复时程以及心房钠尿肽（ANP）、脑钠肽（BNP）、

-肌凝蛋白重链（

-MHC） mRNA表达水平的影响；以PI3K的激活剂3，4，5-三磷酸磷脂酰肌醇（PIP3，1 μmol/L）和舒尼替尼共同干预hiPSC-CMs，考察PI3K在舒尼替尼致心肌收缩功能障碍中的作用。

结果

舒尼替尼对hiPSC-CMs收缩力的抑制作用有浓度依赖趋势，IC

值为3.14 μmol/L。以3.14 μmol/L舒尼替尼干预后，hiPSC-CMs的收缩频率和钙瞬变幅度均显著降低（

＜0.05或

＜0.01），钙瞬变恢复时程显著延长（

＜0.05），ANP、BNP、

-MHC mRNA表达水平均显著升高（

＜0.01）；PIP3激活PI3K后，hiPSC-CMs收缩力显著升高（

＜0.01）。

结论

激活PI3K活性是改善舒尼替尼致心肌毒性的潜在分子机制。

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 IC

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

-myosin heavy chain （

-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. IC

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 （

＜0.05 or

＜0.01）； the duration of calcium transient recovery was prolonged significantly （

＜0.05）， and mRNA expressions of ANP， BNP and

-MHC were significantly increased （

＜0.01）. After PI3K was activated with PIP3， the contractile force of hiPSC-CMs was increased significantly （

＜0.01）.

CONCLUSIONS

Activating PI3K activity is a potential molecular mechanism to improve myocardial toxicity induced by sunitinib.

关键词

舒尼替尼收缩功能障碍心脏毒性磷脂酰肌醇-3-激酶人源诱导型多能干细胞来源的心肌细胞

Keywords

systolic dysfunctioncardiotoxicityphosphatidylinositol-3-kinasehuman induced pluripotent stem cell-derived cardiomyocytes

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