| First Author | Kassan M | Year | 2013 |
| Journal | Diabetes | Volume | 62 |
| Issue | 6 | Pages | 2078-87 |
| PubMed ID | 23349490 | Mgi Jnum | J:208566 |
| Mgi Id | MGI:5563716 | Doi | 10.2337/db12-1374 |
| Citation | Kassan M, et al. (2013) Enhanced NF-kappaB activity impairs vascular function through PARP-1-, SP-1-, and COX-2-dependent mechanisms in type 2 diabetes. Diabetes 62(6):2078-87 |
| abstractText | Type 2 diabetes (T2D) is associated with vascular dysfunction. We hypothesized that increased nuclear factor-kappaB (NF-kappaB) signaling contributes to vascular dysfunction in T2D. We treated type 2 diabetic (db(-)/db(-)) and control (db(-)/db(+)) mice with two NF-kappaB inhibitors (6 mg/kg dehydroxymethylepoxyquinomicin twice a week and 500 mug/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-kappaB inhibitors had significantly reduced myogenic tone potentiation and improved EDR. Importantly, vascular function was also rescued in db(-)/db(-p50NF-kappaB-/-) and db(-)/db(-PARP-1-/-) double knockout mice compared with db(-)/db(-) mice. Additionally, the acute in vitro downregulation of NF-kappaB-p65 using p65NF-kappaB short hairpin RNA lentivirus in arteries from db(-)/db(-) mice also improved vascular function. The NF-kappaB inhibition did not affect blood glucose level or body weight. The RNA levels for Sp-1 and eNOS phosphorylation were decreased, while p65NF-kappaB 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-kappaB inhibition and in db(-)/db(-p50NF-kappaB-/-) and db(-)/db(-PARP-1-/-) mice. In the current study, we provided evidence that enhanced NF-kappaB activity impairs vascular function by PARP-1-, Sp-1-, and COX-2-dependent mechanisms in male type 2 diabetic mice. Therefore, NF-kappaB could be a potential target to overcome diabetes-induced vascular dysfunction. |
