Enhanced NF-κB Activity Impairs Vascular Function Through PARP-1-, SP-1-, and COX-2-Dependent Mechanisms in Type 2 Diabetes

摘要

Type 2 diabetes (T2D) is associated with vascular dysfunction. We hypothesized that increased nuclear factor-KB (NF-kB) signaling contributes to vascular dysfunction in T2D. We treated type 2 diabetic (db~-/db~-) and control (db~-/db~+) mice with two NF-kB inhibitors (6 mg/kg dehydroxymethylepoxyquinomicin twice a week and 500 μg/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-kB inhibitors had significantly reduced myogenic tone potentiation and improved EDR. Importantly, vascular function was also rescued in db~-/db~(-p50NF-κB-/-) and db~-/db~(-PARP-1-/-) double knockout mice compared with db /db mice. Additionally, the acute in vitro downregulation of NF-κB-p65 using p65NF-kB short hairpin RNA lentivirus in arteries from db~-/db~- mice also improved vascular function. The NF-κB inhibition did not affect blood glucose level or body weight The RNA levels for Sp-1 and eNOS phosphorylation were decreased, while p65NF-kB phos-phorylation, cleaved poly(ADP-ribose) polymerase (PARP)-l, and cyclooxygenase (COX)-2 expression were increased in arteries from diabetic mice, which were restored after NF-kB inhibition and in db~-/db~(-p50NF-κB-/-) and db~-/db~(-PARp-1-/-) mice. In the current study, we provided evidence that enhanced NF-kB activity, impairs vascular function by PARP-1-, Sp-1-, and COX-2-dependent mechanisms in male type 2 diabetic mice. Therefore, NF-κB could be a potential target to overcome diabetes-induced vascular dysfunction.