Abstract
PurposePropofol 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).MethodsHuman 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.ResultsTreatment 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.ConclusionsPropofol-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.
Highlights
Propofol infusion syndrome (PRIS) is a rare but lethal condition caused by prolonged propofol overdose [1,2,3]
50 μg/ml propofol resulted in a significant elevation the lactate concentration in the culture media (P = 0.02), and reduction in cell viability (P = 0.04) compared with cells treated with a propofol-free triglyceride emulsion
Our results indicated that PGC-1alpha expression significantly decreased with propofol, and downregulation of nuclear respiratory factor 1/2 (NRF1/2), PPAR-alpha, PDSS1, and carnitine palmitoyltransferase 1B (CPT1B) were observed
Summary
Propofol infusion syndrome (PRIS) is a rare but lethal condition caused by prolonged propofol overdose [1,2,3]. The syndrome is characterized by severe metabolic acidosis, cardiac failure, refractory arrhythmia, hyperlipidemia, hepatomegaly accompanied by fatty liver, renal failure, and rhabdomyolysis [4]. Journal of Anesthesia (2018) 32:120–131 enzyme activity of mitochondrial respiratory chain complexes. Their experimental design used a tissue homogenate preparation including mitochondria-enriched fractions. It remains unknown whether CoQ10 can effectively protect cells and tissues from the toxic effects of propofol
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