Okadaic acid inhibits the trichostatin A-mediated increase of human CYP46A1 neuronal expression in a ERK1/2-Sp3-dependent pathway

Nunes, Maria João; Moutinho, Miguel; Milagre, Inês; Gama, Maria João; Rodrigues, Elsa

doi:10.1194/jlr.m027680

Cited by 11 publications

(6 citation statements)

References 54 publications

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“…The association of CYP46A1 rs10151332 and CYP27A1 rs645163 polymorphisms with both large CCM lesion count and susceptibility to ICH is consistent with a substantial body of evidence indicating that variations in CYPs involved in cholesterol metabolism in the brain, such as the cholesterol 24-hydroxylase CYP46A1 and the sterol 27-hydroxylase CYP27A1, can lead to local excess levels of biologically active 24-OHC and 27-OHC oxysterols [84] , [85] , [112] , [113] , [114] , [115] . Indeed, local accumulation of these cholesterol oxidation derivatives can trigger and sustain local oxidative stress and inflammatory reactions that contribute to distinct human disorders, including cerebrovascular diseases [83] , [86] , [116] .…”

Section: Discussionsupporting

confidence: 78%

Cytochrome P450 and matrix metalloproteinase genetic modifiers of disease severity in Cerebral Cavernous Malformation type 1

Choquet

Trapani

Gallelli

et al. 2016

Free Radical Biology and Medicine

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BackgroundFamilial Cerebral Cavernous Malformation type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and characterized by multiple brain lesions. CCM lesions manifest across a range of different phenotypes, including wide differences in lesion number, size and susceptibility to intracerebral hemorrhage (ICH). Oxidative stress plays an important role in cerebrovascular disease pathogenesis, raising the possibility that inter-individual variability in genes related to oxidative stress may contribute to the phenotypic differences observed in CCM1 disease. Here, we investigated whether candidate oxidative stress-related cytochrome P450 (CYP) and matrix metalloproteinase (MMP) genetic markers grouped by superfamilies, families or genes, or analyzed individually influence the severity of CCM1 disease.MethodsClinical assessment and cerebral susceptibility-weighted magnetic resonance imaging (SWI) were performed to determine total and large (≥5 mm in diameter) lesion counts as well as ICH in 188 Hispanic CCM1 patients harboring the founder KRIT1/CCM1 ‘common Hispanic mutation’ (CCM1–CHM). Samples were genotyped on the Affymetrix Axiom Genome-Wide LAT1 Human Array. We analyzed 1,122 genetic markers (both single nucleotide polymorphisms (SNPs) and insertion/deletions) grouped by CYP and MMP superfamily, family or gene for association with total or large lesion count and ICH adjusted for age at enrollment and gender. Genetic markers bearing the associations were then analyzed individually.ResultsThe CYP superfamily showed a trend toward association with total lesion count (P=0.057) and large lesion count (P=0.088) in contrast to the MMP superfamily. The CYP4 and CYP8 families were associated with either large lesion count or total lesion count (P=0.014), and two other families (CYP46 and the MMP Stromelysins) were associated with ICH (P=0.011 and 0.007, respectively). CYP4F12 rs11085971, CYP8A1 rs5628, CYP46A1 rs10151332, and MMP3 rs117153070 single SNPs, mainly bearing the above-mentioned associations, were also individually associated with CCM1 disease severity.ConclusionsOverall, our candidate oxidative stress-related genetic markers set approach outlined CYP and MMP families and identified suggestive SNPs that may impact the severity of CCM1 disease, including the development of numerous and large CCM lesions and ICH. These novel genetic risk factors of prognostic value could serve as early objective predictors of disease outcome and might ultimately provide better options for disease prevention and treatment.

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Section: Discussionsupporting

confidence: 78%

Cytochrome P450 and matrix metalloproteinase genetic modifiers of disease severity in Cerebral Cavernous Malformation type 1

Choquet

Trapani

Gallelli

et al. 2016

Free Radical Biology and Medicine

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“…In addition, it has been shown that TSA inhibits STAT3-dependent transcriptional activity induced by platelet-derived growth factor (29). On the other hand, exposure to okadaic acid does not affect induction of EC-SOD by scriptaid in HPAECs, whereas a similar exposure to okadaic acid attenuated induction of CYP46A1 gene by TSA in neuroblastoma cells (30).…”

Section: Discussionmentioning

confidence: 98%

Regulation of Oxidative Stress in Pulmonary Artery Endothelium. Modulation of Extracellular Superoxide Dismutase and NOX4 Expression Using Histone Deacetylase Class I Inhibitors

Zelko

Folz

2015

Am J Respir Cell Mol Biol

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An imbalance between oxidants and antioxidants is considered a major factor in the development of pulmonary vascular diseases. Oxidative stress seen in pulmonary vascular cells is regulated by increased expression of prooxidant enzymes (e.g., nicotinamide adenine dinucleotide phosphate reduced oxidases) and/or decreased production of antioxidants and antioxidant enzymes (e.g., superoxide dismutases). We and others have shown that expression of antioxidant genes in pulmonary artery cells is regulated by epigenetic mechanisms. In this study, we investigate the regulation of oxidative stress in pulmonary artery cells using inhibitors of histone deacetylases (HDACs). Human pulmonary artery endothelial cells (HPAECs) and human pulmonary artery smooth muscle cells were exposed to an array of HDAC inhibitors followed by analysis of antiand prooxidant gene expression using quantitative RT-PCR and quantitative RT-PCR array. We found that exposure of HPAECs to scriptaid, N-[4-[(hydroxyamino)carbonyl]phenyl]-a-(1-methylethyl)-benzeneacetamide, and trichostatin A for 24 hours induced expression of extracellular superoxide dismutase (EC-SOD) up to 10-fold, whereas expression of the prooxidant gene NADPH oxidase 4 was decreased by more than 95%. We also found that this differential regulation of anti-and prooxidant gene expression resulted in significant attenuation in the cellular levels of reactive oxygen species. Induction of EC-SOD expression was attenuated by the Janus kinase 2 protein kinase inhibitor AG490 and by silencing Janus kinase 2 expression. Augmentation of EC-SOD expression using scriptaid was associated with increased histone H3 (Lys27) acetylation and H3 (Lys4) trimethylation at the gene promoter. We have determined that oxidative stress in pulmonary endothelial cells is regulated by epigenetic mechanisms and can be modulated using HDAC inhibitors.Keywords: oxidative stress; superoxide dismutase; histone acetylation; endothelial cells; NADPH oxidases Clinical RelevancePulmonary hypertension and pulmonary vascular remodeling are known to be regulated by an imbalance of oxidants and antioxidants and by epigenetic changes in the vascular wall, although the precise signaling pathways involved have not been studied in detail. This study evaluates the role of specific histone modifications in regulation of major pro-and antioxidant enzymes in human pulmonary artery endothelial cells.Increased oxidative stress due to imbalances between prooxidants and antioxidants are associated with cardiovascular pathologies, including pulmonary arterial hypertension and pulmonary vascular remodeling.Oxidative stress is characterized by increased production of superoxide radicals, hydrogen peroxide, and nitric oxide (NO) and/or decreased levels of antioxidants and antioxidant enzymes. Reactive oxygen species (ROS) are produced in the lungs and vascular tissues due to up-regulation of NADPH oxidase (NOX) expression (1), tissue hypoxia, and ischemia (2, 3) or as a result of inflammatory cascade activation

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“…Specificity proteins (SP) 1, 3, 4 appear to be critical for the effect of HDACi – loss of SP3 from the promoter triggers a decrease in the occupancy of HDACs 1 and 2, with subsequent recruitment of CBP and p300 ( Milagre et al, 2012 ). In a subsequent study these authors identified a potential role for MEK - ERK signaling in the regulatory process and provided evidence that pERK is present at the CYP46A1 promoter where it phosphorylates SP3 , thus triggering recruitment of corepressors ( Nunes et al, 2012 ). Given the highly restricted expression of CYP46A1 – in healthy brain it is only present in neurons – this mechanism may represent a supression mechanism important for cell-specificity of CYP46A1 .…”

Section: Cholesterol Eliminationmentioning

confidence: 99%

“…In HepG2 cells, HDACi treatment appears to reduce the expression of the LDL-receptor ( Chittur et al, 2008 ; Nunes et al, 2012 ). In addition, the proprotein convertase subtilisin/kexin type 9 protein ( PCSK9 ), which controls the degradation of the LDL-receptor and is a critical regulator of the amount of LDLR expressed on the cell surface, is epigenetically regulated.…”

Section: Lipoproteinsmentioning

confidence: 99%

Epigenetic regulation of cholesterol homeostasis

Meaney

2014

Front. Genet.

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Although best known as a risk factor for cardiovascular disease, cholesterol is a vital component of all mammalian cells. In addition to key structural roles, cholesterol is a vital biochemical precursor for numerous biologically important compounds including oxysterols and bile acids, as well as acting as an activator of critical morphogenic systems (e.g., the Hedgehog system). A variety of sophisticated regulatory mechanisms interact to coordinate the overall level of cholesterol in cells, tissues and the entire organism. Accumulating evidence indicates that in additional to the more “traditional” regulatory schemes, cholesterol homeostasis is also under the control of epigenetic mechanisms such as histone acetylation and DNA methylation. The available evidence supporting a role for these mechanisms in the control of cholesterol synthesis, elimination, transport and storage are the focus of this review.

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Okadaic acid inhibits the trichostatin A-mediated increase of human CYP46A1 neuronal expression in a ERK1/2-Sp3-dependent pathway

Cited by 11 publications

References 54 publications

Cytochrome P450 and matrix metalloproteinase genetic modifiers of disease severity in Cerebral Cavernous Malformation type 1

Cytochrome P450 and matrix metalloproteinase genetic modifiers of disease severity in Cerebral Cavernous Malformation type 1

Regulation of Oxidative Stress in Pulmonary Artery Endothelium. Modulation of Extracellular Superoxide Dismutase and NOX4 Expression Using Histone Deacetylase Class I Inhibitors

Epigenetic regulation of cholesterol homeostasis

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