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Cytotoxicity of propofol in human induced pluripotent stem cell-derived cardiomyocytes.
J Anesth. 2018 02; 32(1):120-131.JA

Abstract

PURPOSE

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).

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

Authors+Show Affiliations

Department of Anesthesiology, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. kidomane@tmd.ac.jp.Department of Anesthesiology, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.Department of Anesthesiology, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.Division of Anesthesia, Kyoundo Hospital, Tokyo, Japan.Department of Anesthesiology, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29288336

Citation

Kido, Koji, et al. "Cytotoxicity of Propofol in Human Induced Pluripotent Stem Cell-derived Cardiomyocytes." Journal of Anesthesia, vol. 32, no. 1, 2018, pp. 120-131.
Kido K, Ito H, Yamamoto Y, et al. Cytotoxicity of propofol in human induced pluripotent stem cell-derived cardiomyocytes. J Anesth. 2018;32(1):120-131.
Kido, K., Ito, H., Yamamoto, Y., Makita, K., & Uchida, T. (2018). Cytotoxicity of propofol in human induced pluripotent stem cell-derived cardiomyocytes. Journal of Anesthesia, 32(1), 120-131. https://doi.org/10.1007/s00540-017-2441-0
Kido K, et al. Cytotoxicity of Propofol in Human Induced Pluripotent Stem Cell-derived Cardiomyocytes. J Anesth. 2018;32(1):120-131. PubMed PMID: 29288336.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cytotoxicity of propofol in human induced pluripotent stem cell-derived cardiomyocytes. AU - Kido,Koji, AU - Ito,Hiroyuki, AU - Yamamoto,Yudai, AU - Makita,Koshi, AU - Uchida,Tokujiro, Y1 - 2017/12/29/ PY - 2017/07/07/received PY - 2017/12/16/accepted PY - 2017/12/31/pubmed PY - 2019/4/23/medline PY - 2017/12/31/entrez KW - Cardiomyocytes KW - Cytotoxicity KW - Induced pluripotent stem cells KW - Mitochondrial dysfunction KW - Propofol SP - 120 EP - 131 JF - Journal of anesthesia JO - J Anesth VL - 32 IS - 1 N2 - PURPOSE: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. SN - 1438-8359 UR - https://www.unboundmedicine.com/medline/citation/29288336/Cytotoxicity_of_propofol_in_human_induced_pluripotent_stem_cell_derived_cardiomyocytes_ L2 - https://dx.doi.org/10.1007/s00540-017-2441-0 DB - PRIME DP - Unbound Medicine ER -