期刊
JOURNAL OF APPLIED TOXICOLOGY
卷 41, 期 4, 页码 618-631出版社
WILEY
DOI: 10.1002/jat.4070
关键词
apoptosis; cardiomyocytes; FOXO3a; MEHP; oxidative stress
类别
资金
- Key R&D Program Project of Hebei Province [19274801D]
- Educational Commission of Hebei Province, China [ZD2019044]
- Natural Science Foundation of Hebei Province of PR China [B2018206283]
- National Natural Science Foundation of China [21976050, 81473292, 21507022]
The cardiotoxicity of MEHP is mediated by reduced cell viability, mitochondrial dysfunction, oxidative stress, and apoptosis in cardiomyocytes. FOXO3a plays a critical role in defending against MEHP-induced oxidative stress and apoptosis by upregulating the expression of Mn-SOD and ARC.
Mono(2-ethylhexyl)phthalate (MEHP), the active metabolite of di(2-ethylhexyl)phthalate (DEHP), is known to exert cardiotoxicity. The aim of the present study was to investigate the role of forkhead box O3a (FOXO3a) in MEHP-induced human AC16 cardiomyocyte injuries. MEHP reduced cell viability and mitochondrial membrane potential (Delta psi m), whereas it increased lactate dehydrogenase (LDH) leakage, production of reactive oxygen species (ROS), and apoptosis in cardiomyocytes. The expression of FOXO3a and its target genes, mitochondrial superoxide dismutase (Mn-SOD) and apoptosis repressor with caspase recruitment domain (ARC), increased after MEHP exposure, but the expression of p-FOXO3a protein was decreased. Overexpression of FOXO3a decreased the production of ROS and the apoptosis rate induced by MEHP, and the expression of Mn-SOD and ARC was further increased after MEHP exposure. In contrast, knockdown of FOXO3a resulted in increased ROS production and apoptosis and suppressed the expression of Mn-SOD and ARC in the presence of MEHP. However, overexpression or knockdown of FOXO3a did not affect MEHP-induced loss of Delta psi m. In conclusion, the loss of Delta psi m and apoptosis are involved in MEHP-induced cardiomyocyte toxicity. Activation of FOXO3a defends against MEHP-induced oxidative stress and apoptosis by upregulating the expression of Mn-SOD and ARC in AC16 cardiomyocytes.
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