Abstract 137: Nuclear factor kappa B (NFκB) activation Impairs Vascular Endothelial Function in Type 2 Diabetic Mice

Abstract

Rationale and Objective: 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. Methods and results: Type 2 diabetic (db - /db - ) and control (db - /db + ) mice were treated with two NFκB inhibitors (DHMEQ, 6mg/kg, twice a week and IKK-NBD peptide, 500μg/kg/day) for four weeks. Pressure-induced myogenic tone (MT) was significantly potentiated, while endothelium-dependent relaxation (EDR) was impaired in coronary arteriole (CA), mesenteric resistance artery (MRA) and aorta 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 double knockout mice between db - /db - and NFκB-p50 -/- (db - /db -p-50NFκB-/- ) and PARP-1 -/- (db - /db -PARP-1-/- ) compared to db - /db - mice. In addition, the acute in vitro down regulation of NFκB-p65 using shRNA-lentivirus-p65 in arteries from db - /db - mice also improved vascular function. The NFκB inhibition did not affect blood glucose and body weight. The expression of Sp-1 was decreased in diabetic mice and restored with NFκB inhibition. Western blot analysis revealed a decrease in eNOS phosphorylation, and an increase in p65 -NFκB phosphorylation, cleaved PARP-1 and COX-2 expression in arteries from diabetic mice, which were rescued after NFκB inhibition and in db - /db -p-50NFκB-/- and db - /db -PARP-1-/- mice. Conclusion: 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.