Enhanced NF-κB 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-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 μg/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(-)/db(-p50NF-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.
Department of Physiology, Hypertension and Renal Center of Excellence, Tulane University, New Orleans, Louisiana, USA.
Modar
M
Kassan
Soo-Kyoung
SK
Choi
Maria
M
Galán
Alexander
A
Bishop
Kazuo
K
Umezawa
Mohamed
M
Trebak
Souad
S
Belmadani
Khalid
K
Matrougui
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D003512:Cyclohexanones / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*
D001549:Benzamides; D003512:Cyclohexanones; D016328:NF-kappa B; D016329:Sp1 Transcription Factor; C464444:dehydroxymethylepoxyquinomicin; D051546:Cyclooxygenase 2; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases