Nuclear Factor kappa B (NFkB) Inhibition Improves Vascular Function in Type 2 Diabetic Mice

Abstract

Type 2 diabetes (T2D) is associated with microvascular dysfunction. We hypothesized that increased NFκB signaling contributes to vascular dysfunction in T2D. 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, 500ug/kg/day) for four weeks. Isolated coronary arterioles (CA) and mesenteric resistance arteries (MRA) were mounted in an arteriograph and a myograph. Pressure‐induced myogenic tone (MT) was significantly potentiated, while endothelium‐dependent relaxation (EDR) was significantly attenuated in CA and MRA from diabetic compared to control mice. These results were associated with increased NFκB activity. Interestingly, diabetic mice treated with NFκB inhibitors significantly reduced MT potentiation and improved EDR. Western blot analysis revealed a decrease in eNOS expression and phosphorylation, increase in p‐65NFκB phosphorylation and COX2 expression in diabetic mice, which were normalized with NFκB inhibition. Thus, we demonstrated that increased NFκB activity disrupts the basic mechanism of microvascular function in T2D. Therefore, NFκB could be a potential target to overcome diabetic microvascular complications.