Enhanced NF-?B activity impairs vascular function through PARP-1-, SP-1-, and COX-2-dependent mechanisms in type 2 diabetes.

ABSTRACT: Type 2 diabetes (T2D) is associated with vascular dysfunction. We hypothesized that increased nuclear factor-?B (NF-?B) signaling contributes to vascular dysfunction in T2D. We treated type 2 diabetic (db(-)/db(-)) and control (db(-)/db(+)) mice with two NF-?B inhibitors (6 mg/kg dehydroxymethylepoxyquinomicin twice a week and 500 ?g/kg/day IKK-NBD peptide) for 4 weeks. Pressure-induced myogenic tone was significantly potentiated, while endothelium-dependent relaxation (EDR) was impaired in small coronary arterioles and mesenteric resistance artery from diabetic mice compared with controls. Interestingly, diabetic mice treated with NF-?B inhibitors had significantly reduced myogenic tone potentiation and improved EDR. Importantly, vascular function was also rescued in db(-)/db(-p50NF-?B-/-) and db(-)/db(-PARP-1-/-) double knockout mice compared with db(-)/db(-) mice. Additionally, the acute in vitro downregulation of NF-?B-p65 using p65NF-?B short hairpin RNA lentivirus in arteries from db(-)/db(-) mice also improved vascular function. The NF-?B inhibition did not affect blood glucose level or body weight. The RNA levels for Sp-1 and eNOS phosphorylation were decreased, while p65NF-?B phosphorylation, cleaved poly(ADP-ribose) polymerase (PARP)-1, and cyclooxygenase (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 current 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.

SUBMITTER: Kassan M 

PROVIDER: S-EPMC3661639 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature