Mitochondrial activity and oxidative stress functions are influenced by the activation of AhR-induced CYP1A1 overexpression in cardiomyocytes

Abstract

There is an endemic cardiomyopathy currently occurring in China, termed, Keshan disease (KD). The authors previously compared mitochondrial-associated gene expression profiles of peripheral blood mononuclear cells (PBMCs) derived from KD patients and normal controls, using mitochondria-focused cDNA microarray technology. The results detected an upregulation of the enzyme-associated CYP1A1 gene, (ratios ≥2.0). The aryl hydrocarbon receptor (AhR) regulates the expression of numerous cytochrome P450 (CYP) genes including members of the CYP1 family; CYP1A1 and CYP1A2. Several previous studies have suggested roles for the aryl hydrocarbon receptor (AhR) and the genes that it regulates. An example involves cytochrome P4501A1 (CYP1A1), in the pathogenesis of heart failure, cardiac hypertrophy and other cardiomyopathies. Mitochondria comprise ~30% of the intracellular volume in mammalian cardiomyocytes, and subtle alterations in mitochondria can markedly influence cardiomyopathies. The present study investigated alterations in the activity and functions of mitochondria following AhR-induced overexpression of CYP1A1. AC16 cells were treated with the CYP1A1 inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and cytotoxicity was then evaluated in MTT assays. Reverse transcription-quantitative polymerase chain reactions, western blot analysis and 7-ethoxyresorufin O-deacylase assays were performed to analyze the mRNA and protein levels, and the enzymatic activity of CYP1A1. Mitochondrial activity and mass were analyzed using an inverted fluorescence microscope and a fluorescence microplate reader. Reactive oxygen species (ROS) activity was analyzed using flow cytometry. The results of the current study demonstrated that TCDD gradually increased mRNA and protein levels of AhR and CYP1A1, in addition to the enzymatic activity. Mitochondrial activity and the quality of mitochondrial membranes were also significantly attenuated, and mitochondrial ROS levels were elevated in the TCDD-induced cardiomyocytes. The results indicate the involvement of the AhR/CYP1A1 signaling pathway in the mechanism of action of TCDD in human cardiomyocytes. The present findings may provide an explanation for myocardial injuries caused by polycyclic aromatic hydrocarbons. The authors conclude that exposure to TCDD results in regulatory alteration to the expression of detoxification genes that ultimately affect the metabolic activation and function of cardiomyocytes.

Particulate matter-induced senescence of skin keratinocytes involves oxidative stress-dependent epigenetic modifications

“…PAHs interact directly with AhR, promoting AhR translocation into the nucleus and leading to ROS production 27 . We thus hypothesized that PM 2.5 -induced cellular senescence might occur via the AhR–ROS signaling pathway.…”

AhR and IDO1 in pathogenesis of Covid-19 and the “Systemic AhR Activation Syndrome:” a translational review and therapeutic perspectives

“…During late phase of the disease, cytokine elevation related to persistent activation of AhRs by CoV, can also induce tissue injury in diverse organs, and contribute to worsening of clinical manifestations and disease outcomes. Cardiomyocytes exposed to TCDD, an AhR agonist, also respond with increasing CYP1A1 mRNA and protein expression in an AhR dependent manner suggesting activation of the AhR/CYP1A1 signaling pathway ( Zhou et al, 2017 ). Therefore, we hypothesize, that the AhR/CYP1 signaling pathway may be activated by CoV in organs undergoing tissue injuries during both early and late stages of disease, and that elevated cytokines such as IL-6, IL-8 or IL-1ß ( Leisman, Deutschman, & Legrand, 2020 ) may activate diverse signal cascades causing and accelerating tissue injury.…”

Kebar grass (Biophytum petersianum K.) The effect inmaintaining mice (Mus musculus) sperm quality exposed to dioxin

“…Excessive expression of cytochrome p450 can cause spermatogenic cell death. According to Zhou et al (2017), TCDD gradually increased mRNA and protein levels of AhR and CYP1A1, in addition to the enzymatic activity. Mitochondrial activity and the mitochondrial membrane quality were also signi icantly attenuated, and ROS levels were elevated.…”