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- Title
Enhanced NF-κB Activity Impairs Vascular Function Through PARP-1-, SP-1-, and COX-2-Dependent Mechanisms in Type 2 Diabetes.
- Authors
Kassan, Modar; Soo-Kyoung Choi; Galán, Maria; Bishop, Alexander; Umezawa, Kazuo; Trebak, Mohamed; Belmadani, Souad; Matrougui, Khalid
- Abstract
Type 2 diabetes (T2D) is associated with vascular dysfunction. We hypothesized that increased nuclear factor-κB (NF-κB) signaling contributes to vascular dysfunction in T2D. We treated type 2 diabetic (db-/db-) and control (db-/db+) mice with two NF-κB 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-κB inhibitors had significantly reduced myogenic tone potentiation and improved EDR. Importantly, vascular function was also rescued in db-/d-2p50NF-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-κB 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-κB 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-κB inhibition and in db-/db-p50NF-κB-/- and db-/db-PARP-1-/- mice. In the current study, we provided evidence that enhanced NF-κB 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.
- Subjects
TYPE 2 diabetes; LABORATORY mice; MYOBLASTS; LENTIVIRUS diseases; LENTIVIRUSES
- Publication
Diabetes, 2013, Vol 62, Issue 6, p2078
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db12-1374