| Enhanced NFκB Activity Impairs Vascular Function through PARP-1, SP-1 and COX2-Dependent Mechanisms in Type 2 Diabetes. | |
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MedLine Citation:
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PMID: 23349490 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Type 2 diabetes (T2D) is associated with vascular dysfunction. We hypothesized that increased nuclear factor kappa B (NFκB) signaling contributes to vascular dysfunction in T2D. We have treated type 2 diabetic (db(-)/db(-)) and control (db(-)/db(+)) mice with two NFκB inhibitors (DHMEQ, 6mg/kg, twice a week and IKK-NBD peptide, 500 μg/kg/day) for four weeks. Pressure-induced myogenic tone (MT) was significantly potentiated, while endothelium dependent relaxation (EDR) was impaired in small coronary arterioles (CA) and mesenteric resistance artery (MRA) from diabetic mice compared to control. Interestingly, diabetic mice treated with NFκB inhibitors significantly reduced MT potentiation and improved EDR. Importantly, vascular function was also rescued in db(-)/db(-p50NFκB-/-) and db(-)/db(-PARP-1-/-) double knockout mice compared to db(-)/db(-) mice. Additionally, the acute in vitro down regulation of NFκB-p65 using p65NFκB shRNA lentivirus in arteries from db(-)/db(-) mice also improved vascular function. The NFκB inhibition did not affect blood glucose level and body weight. The RNA levels for Sp-1 and eNOS phosphorylation were decreased, while p65NFκB phosphorylation, cleaved PARP-1 and COX-2 expression were increased in arteries from diabetic mice, which were restored after NFκB inhibition and in db(-)/db(-p50NFκB-/-) and db(-)/db(-PARP-1-/-) mice.In the present study, we provided evidence that enhanced NFκB activity impairs vascular function by PARP-1, Sp-1 and COX-2-dependent mechanisms in male type 2 diabetic mice. Therefore, NFκB could be a potential target to overcome diabetes-induced vascular dysfunction. |
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Authors:
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Modar Kassan; Soo-Kyoung Choi; Maria Galan; Alexander Bishop; Kazuo Umezawa; Mohamed Trebak; Souad Belmadani; Khalid Matrougui |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2013-1-24 |
Journal Detail:
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Title: Diabetes Volume: - ISSN: 1939-327X ISO Abbreviation: Diabetes Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-1-25 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0372763 Medline TA: Diabetes Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Tulane University, New orleans, Louisiana, United States. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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