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

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 mg/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/db2p50NF-kB2/2 and db/db double knockout mice compared with db/db mice. Additionally, the acute in vitro downregulation of NF-kB–p65 using p65NF-kB short hairpin RNA lentivirus in arteries from db/db mice also improved vascular function. The NF-kB inhibition did not affect blood glucose level or body weight. The RNA levels for Sp-1 and eNOS phosphorylation were decreased, while p65NF-kB 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-kB inhibition and in db/db and db/db 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-kB could be a potential target to overcome diabetes-induced vascular dysfunction. Diabetes 62:2078–2087, 2013