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Parveen Abidi Department of Veterans Affairs Palo Alto Health Care System, Division of Gastroenterology and Hepatology, Department of Immunology, Geriatric Research, Education and Clinical Center (GRECC), 3801 Miranda Avenue, Palo Alto, California 94304, USA

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Haiyan Zhang Department of Veterans Affairs Palo Alto Health Care System, Division of Gastroenterology and Hepatology, Department of Immunology, Geriatric Research, Education and Clinical Center (GRECC), 3801 Miranda Avenue, Palo Alto, California 94304, USA

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Syed M Zaidi Department of Veterans Affairs Palo Alto Health Care System, Division of Gastroenterology and Hepatology, Department of Immunology, Geriatric Research, Education and Clinical Center (GRECC), 3801 Miranda Avenue, Palo Alto, California 94304, USA

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Wen-Jun Shen Department of Veterans Affairs Palo Alto Health Care System, Division of Gastroenterology and Hepatology, Department of Immunology, Geriatric Research, Education and Clinical Center (GRECC), 3801 Miranda Avenue, Palo Alto, California 94304, USA

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Susan Leers-Sucheta Department of Veterans Affairs Palo Alto Health Care System, Division of Gastroenterology and Hepatology, Department of Immunology, Geriatric Research, Education and Clinical Center (GRECC), 3801 Miranda Avenue, Palo Alto, California 94304, USA

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Yuan Cortez Department of Veterans Affairs Palo Alto Health Care System, Division of Gastroenterology and Hepatology, Department of Immunology, Geriatric Research, Education and Clinical Center (GRECC), 3801 Miranda Avenue, Palo Alto, California 94304, USA

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Jiahuai Han Department of Veterans Affairs Palo Alto Health Care System, Division of Gastroenterology and Hepatology, Department of Immunology, Geriatric Research, Education and Clinical Center (GRECC), 3801 Miranda Avenue, Palo Alto, California 94304, USA

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Salman Azhar Department of Veterans Affairs Palo Alto Health Care System, Division of Gastroenterology and Hepatology, Department of Immunology, Geriatric Research, Education and Clinical Center (GRECC), 3801 Miranda Avenue, Palo Alto, California 94304, USA
Department of Veterans Affairs Palo Alto Health Care System, Division of Gastroenterology and Hepatology, Department of Immunology, Geriatric Research, Education and Clinical Center (GRECC), 3801 Miranda Avenue, Palo Alto, California 94304, USA

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Previous studies from this laboratory identified excessive oxidative stress as an important mediator of age-related decline in steroid hormone production. Here, we investigated whether oxidative stress exerts its antisteroidogenic action through modulation of oxidant-sensitive mitogen-activated protein kinase (MAPK) signaling pathways. To accomplish these studies, we employed a highly responsive mouse adrenocortical cell line, Y1-BS1 cells that secrete large quantities of steroids when stimulated with lipoprotein plus hormone. Treatment of these cells with superoxide, H2O2 or 4-hydroxy-2-nonenal (HNE) significantly inhibited steroid production and increased phosphorylation and activation of p38 MAPK. None of the treatments altered the phosphorylation of either extracellular signal-regulated kinases or c-Jun N-terminal kinases (JNKs). Pretreatment of Y1-BS1 cells with MnTMPyP, a cell-permeable superoxide-dismutase/catalase mimetic reactive oxygen species (ROS scavenger), completely prevented the superoxide- and H2O2-mediated inhibition of steroid production. Likewise, antioxidant N-acetylcysteine completely blocked the HNE-induced loss of steroidogenic response. Incubation of Y1-BS1 cells with either MnTMPyP or NAC also upregulated Bt2cAMP and Bt2cAMP+hHDL3-stimulated steroid synthesis, indicating that endogenously produced ROS can inhibit steroidogenesis. Inhibition of p38 MAPK with SB203580 or SB202190 upregulated the basal steroid production and also prevented the oxidant-mediated inhibition of steroid production. mRNA measurements by qPCR indicated that Y1-BS1 adrenal cells predominantly express p38 MAPKα isoform, along with relatively low-level expression of p38 MAPKγ. By contrast, little or no expression was detected for p38 MAPKβ and p38 MAPKδ isoforms in these cells. Transfection of Y1-BS1 cells with either caMKK3 or caMMK6 construct, the upstream p38 MAPK activators, decreased steroidogenesis, whereas transfection with dnMKK3 or dnMKK6 plasmid DNA increased steroidogenesis. Similarly, transfection of cells with a dnp38 MAPKα or dnp38 MAPKβ construct also increased steroid hormone production; however, the effect was less pronounced after expression of either dnp38 MAPKγ or dnp38 MAPKδ construct. These results indicate that activated p38 MAPK mediates oxidant (excessive oxidative stress)-induced inhibition of adrenal steroidogenesis.

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