CoCl₂ Decreases EC-SOD Expression through Histone Deacetylation in COS7 Cells

Abstract

Extracellular-superoxide dismutase (EC-SOD), one of the SOD isozymes, is negatively regulated under hypoxic conditions, and decreases in its expression may exacerbate vascular diseases. Moreover, epigenetics, such as DNA methylation and histone modifications, are known to play a critical role in the progression of cancer, type 2 diabetes, and atherosclerosis. We previously investigated the involvement of reactive oxygen species (ROS) and p38 mitogen-activated protein kinase (MAPK) in decreases in EC-SOD expression in hypoxic COS7 cells; however, the role of epigenetics in this process currently remains unknown. In the present study, we demonstrated that the hypoxia mimetic cobalt chloride (CoCl 2 ) decreased histone acetylation levels, and a pretreatment with 4-phenyl butyric acid (PBA), an inhibitor of histone deacetylase, significantly suppressed CoCl 2 -elicited histone deacetylation and decreases in EC-SOD. We found that CoCl 2 -elicited decreases in EC-SOD were accompanied by reductions in histone H3 acetylation levels within its promoter region. Furthermore, luteolin, a well-known flavonoid, significantly suppressed the CoCl 2 -elicited accumulation of ROS, p38-MAPK activation, and histone deacetylation. Collectively, the results of the present study showed for the first time that CoCl 2 decreases the expression of EC-SOD through its deacetylation and luteolin may be one of the seed compounds that maintain redox homeostasis, even under hypoxic conditions.

Cobalt chloride toxicity elicited hypertension and cardiac complication via induction of oxidative stress and upregulation of COX-2/Bax signaling pathway

“…45 Furthermore, the inhibitory effect of CoCl 2 on antioxidant enzymes has been reported elsewhere. 46,47 Also, in this study, the sulfhydryl thiol content and AOPP increased significantly in renal tissues of rats exposed to 600 ppm of CoCl 2 . Thiol containing antioxidants such as N-acetyl-L-cysteine have been reported to mitigate drug and toxicant-induced oxidative stress-mediated injuries and prevented the depletion of hepatic and plasma GSH level by scavenging intracellular ROS.…”

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“…The importance of the HIF-1α-dependent epigenetic mechanisms induced by cobalt and other heavy metals is also recognized. It was also shown that stimulation of cobalt dichloride with extracellular matrix deposits, as well as induction of vascular endothelial growth factor and erythropoietin were associated with HIF-1α [70]. In our opinion, the scientific novelty of the proposed approach consists in the fact that for the first time the pathogenesis of deadly oncological diseases induced by heavy metals was explained and based on epigenetic mechanisms for controlling of gene expression.…”

Modern Aspects of Regulatory, Pathophysiological and Toxic Effects of Cobalt Ions During Oral Intake in the Human Body

“…Признается важность HIF-1α-зависимых эпигенетических механизмов, индуцируемых кобальтом и другими тяжелыми металлами. Показано, что стимуляция двухлористого кобальта внеклеточными матричными отложениями, а также индукция фактора роста сосудистого эндотелия и эритропоэтина связаны с HIF-1α [70]. По нашему мнению, научная новизна предлагаемого подхода состоит в том, что впервые объясняется патогенез смертельных онкологических заболеваний, вызываемых тяжелыми металлами, а его возникновение обусловлено эпигенетическими механизмами контроля над экспрессией генов.…”