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• W2212198993 abstract "Abstract Subjects carrying the T2238C ANP gene variant have a higher risk to suffer a stroke or myocardial infarction. The mechanisms through which T2238C/ α ANP exerts detrimental vascular effects need to be fully clarified. In the present work we aimed at exploring the impact of C2238/ α ANP (mutant form) on atherosclerosis-related pathways. As a first step, an atherosclerosis gene expression macroarray analysis was performed in vascular smooth muscle cells (VSMCs) exposed to either T2238/ α ANP (wild type) or C2238/ α ANP. The major finding was that apolipoprotein E ( ApoE ) gene expression was significantly downregulated by C2238/ α ANP and it was upregulated by T2238/ α ANP. We subsequently found that C2238/ α ANP induces ApoE downregulation through type C natriuretic peptide receptor (NPR-C)-dependent mechanisms involving the upregulation of miR199a-3p and miR199a-5p and the downregulation of DNAJA4. In fact, NPR-C knockdown rescued ApoE level. Upregulation of miR199a by NPR-C was mediated by a reactive oxygen species-dependent increase of the early growth response protein-1 (Egr-1) transcription factor. In fact, Egr-1 knockdown abolished the impact of C2238/ α ANP on ApoE and miR199a. Of note, downregulation of ApoE by C2238/ α ANP was associated with a significant increase in inflammation, apoptosis and necrosis that was completely rescued by the exogenous administration of recombinant ApoE. In conclusion, our study dissected a novel mechanism of vascular damage exerted by C2238/ α ANP that is mediated by ApoE downregulation. We provide the first demonstration that C2238/ α ANP downregulates ApoE in VSMCs through NPR-C-dependent activation of Egr-1 and the consequent upregulation of miR199a. Restoring ApoE levels could represent a potential therapeutic strategy to counteract the harmful effects of C2238/ α ANP." @default.
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• W2212198993 date "2015-12-31" @default.
• W2212198993 modified "2023-10-06" @default.
• W2212198993 title "C2238/αANP modulates apolipoprotein E through Egr-1/miR199a in vascular smooth muscle cells in vitro" @default.
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• W2212198993 doi "https://doi.org/10.1038/cddis.2015.370" @default.
• W2212198993 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4720902" @default.
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