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  • Title: Hypobaric hypoxia induced arginase expression limits nitric oxide availability and signaling in rodent heart.
    Author: Singh M, Padhy G, Vats P, Bhargava K, Sethy NK.
    Journal: Biochim Biophys Acta; 2014 Jun; 1840(6):1817-24. PubMed ID: 24440670.
    Abstract:
    BACKGROUND: This study was aimed to evaluate regulation of cardiac arginase expression during hypobaric hypoxia and subsequent effect on nitric oxide availability and signaling. METHODS: Rats were exposed to hypobaric hypoxia (282mmHg for 3h) and ARG1 expression was monitored. The expression levels of eNOS and eNOS(Ser1177) were determined by Western blotting, cGMP levels were measured by ELISA and amino acid concentrations were measured by HPLC analysis. Transcription regulation of arginase was monitored by chromatin immunoprecipitation (ChIP) assay with anti-c-Jun antibody for AP-1 consensus binding site on ARG1 promoter. Arginase activity was inhibited by intra-venous dose of N-(ω)-hydroxy-nor-l-arginine (nor-NOHA) prior to hypoxia exposure and subsequent effect on NO availability and oxidative stress were evaluated. RESULTS: Hypobaric hypoxia induced cardiac arginase expression by recruiting c-Jun to AP-1 binding site on ARG1 promoter. This increased expression redirected l-arginine towards arginase and resulted in limited endothelial nitric oxide synthase (eNOS) activity, nitric oxide (NO) availability and cGMP mediated signaling. Inhibition of arginase restored the eNOS activity, promoted cardiac NO availability and ameliorated peroxynitrite formation during hypoxia. CONCLUSIONS: Hypoxic induced arginase under transcription control of AP-1 reciprocally regulates eNOS activity and NO availability in the heart. This also results in cardiac oxidative stress. GENERAL SIGNIFICANCE: This study provides understanding of hypoxia-mediated transcriptional regulation of arginase expression in the heart and its subsequent effect on eNOS activity, NO availability and signaling as well as cardiac oxidative stress. This information will support the use of arginase inhibitors as therapeutics for pathological hypoxia.
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