Cytotoxicity of propofol in human induced pluripotent stem cell-derived cardiomyocytes.
Cytotoxicity of propofol in human induced pluripotent stem cell-derived cardiomyocytes.
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DOI：
10.1007/s00540-017-2441-0
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发表时间：
2018-03
影响因子：
2.8
通讯作者：
Uchida T
中科院分区：
文献类型：
--
作者：
Kido K;Ito H;Yamamoto Y;Makita K;Uchida T
异丙酚输注综合征（PRIS）是由异丙酚过量引起的致死性疾病。以往的研究表明，PRIS的病理生理机制涉及线粒体功能障碍，然而，这些机制尚未完全阐明。本研究旨在建立丙泊酚诱导的心肌细胞毒性实验模型，探讨丙泊酚诱导心肌细胞线粒体功能障碍的机制，并评价辅酶Q10（CoQ10）的保护作用。将人iPSC衍生的心肌细胞暴露于丙泊酚（0、2、10或50 μ g/ml），含或不含5 μ M CoQ10。通过测量细胞内ATP、培养基中的乳酸浓度、NAD +/NADH比率和线粒体膜电位来评估线粒体功能。通过分析细胞活力来评价丙泊酚诱导的细胞毒性。通过PCR检测线粒体能量代谢相关基因的表达水平。共聚焦显微镜观察细胞内形态学变化。用50 μ g/ml丙泊酚处理48小时可降低细胞活力。高浓度丙泊酚（≥ 10 µ g/ml）诱导线粒体功能障碍，伴有PGC-1 α及其下游靶点（参与呼吸链反应的NDUFS 8和SDHB;以及调节β-氧化的CPT 1B）基因表达下调。用5 μ M CoQ10共处理的心肌细胞通过恢复基因表达表现出对丙泊酚诱导的毒性的抗性。丙泊酚诱导的人iPSC衍生心肌细胞的细胞毒性可能与线粒体功能障碍有关，通过下调PGC-1 α调节基因与线粒体能量代谢相关。CoQ10的共同治疗保护心肌细胞免受丙泊酚诱导的细胞毒性。
Propofol infusion syndrome (PRIS) is a lethal condition caused by propofol overdose. Previous studies suggest that pathophysiological mechanisms underlying PRIS involve mitochondrial dysfunction; however, these mechanisms have not been fully elucidated. This study aimed to establish an experimental model of propofol-induced cytotoxicity using cultured human induced pluripotent stem cell (iPSC)-derived cardiomyocytes to determine the mechanisms behind propofol-induced mitochondrial dysfunction, and to evaluate the protective effects of coenzyme Q10 (CoQ10). Human iPSC-derived cardiomyocytes were exposed to propofol (0, 2, 10, or 50 µg/ml) with or without 5 µM CoQ10. Mitochondrial function was assessed by measuring intracellular ATP, lactate concentrations in culture media, NAD+/NADH ratio, and the mitochondrial membrane potential. Propofol-induced cytotoxicity was evaluated by analysis of cell viability. Expression levels of genes associated with mitochondrial energy metabolism were determined by PCR. Intracellular morphological changes were analyzed by confocal microscopy. Treatment with 50 µg/ml propofol for 48 h reduced cell viability. High concentrations of propofol (≥ 10 µg/ml) induced mitochondrial dysfunction accompanied by downregulation of gene expression of PGC-1alpha and its downstream targets (NDUFS8 and SDHB, which are involved in the respiratory chain reaction; and CPT1B, which regulates beta-oxidation). Cardiomyocytes co-treated with 5 µM CoQ10 exhibited resistance to propofol-induced toxicity through recovery of gene expression. Propofol-induced cytotoxicity in human iPSC-derived cardiomyocytes may be associated with mitochondrial dysfunction via downregulation of PGC-1alpha-regulated genes associated with mitochondrial energy metabolism. Co-treatment with CoQ10 protected cardiomyocytes from propofol-induced cytotoxicity.
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影响因子：
8.8
作者：
dos Santos, Claudia C.;Gattas, David J.;Parker, Thomas G.
通讯作者：
Parker, Thomas G.
影响因子：
3.8
作者：
Cohen JD;Babiarz JE;Abrams RM;Guo L;Kameoka S;Chiao E;Taunton J;Kolaja KL
通讯作者：
Kolaja KL
影响因子：
5.7
作者：
Canfield SG;Zaja I;Godshaw B;Twaroski D;Bai X;Bosnjak ZJ
通讯作者：
Bosnjak ZJ
影响因子：
9.3
作者：
Bullon, Pedro;Roman-Malo, Lourdes;Corder, Mario D.
通讯作者：
Corder, Mario D.
影响因子：
8.8
作者：
Canfield SG;Sepac A;Sedlic F;Muravyeva MY;Bai X;Bosnjak ZJ
通讯作者：
Bosnjak ZJ