Enhanced NF?B Activity Impairs Vascular Function through PARP-1, SP-1 and COX2-Dependent Mechanisms in Type 2 Diabetes.
Diabetes. 2013 Jan 24;
Authors: Kassan M, Choi SK, Galan M, Bishop A, Umezawa K, Trebak M, Belmadani S, Matrougui K
Abstract
Type 2 diabetes (T2D) is associated with vascular dysfunction. We hypothesized that increased nuclear factor kappa B (NF?B) signaling contributes to vascular dysfunction in T2D. We have treated type 2 diabetic (db(-)/db(-)) and control (db(-)/db(+)) mice with two NF?B inhibitors (DHMEQ, 6mg/kg, twice a week and IKK-NBD peptide, 500 ?g/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 NF?B inhibitors significantly reduced MT potentiation and improved EDR. Importantly, vascular function was also rescued in db(-)/db(-p50NF?B-/-) and db(-)/db(-PARP-1-/-) double knockout mice compared to db(-)/db(-) mice. Additionally, the acute in vitro down regulation of NF?B-p65 using p65NF?B shRNA lentivirus in arteries from db(-)/db(-) mice also improved vascular function. The NF?B inhibition did not affect blood glucose level and body weight. The RNA levels for Sp-1 and eNOS phosphorylation were decreased, while p65NF?B phosphorylation, cleaved PARP-1 and COX-2 expression were increased in arteries from diabetic mice, which were restored after NF?B inhibition and in db(-)/db(-p50NF?B-/-) and db(-)/db(-PARP-1-/-) mice.In the present study, we provided evidence that enhanced NF?B activity impairs vascular function by PARP-1, Sp-1 and COX-2-dependent mechanisms in male type 2 diabetic mice. Therefore, NF?B could be a potential target to overcome diabetes-induced vascular dysfunction.
PMID: 23349490 [PubMed - as supplied by publisher]
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