Enhanced NF-κB activity impairs vascular function through PARP-1-, SP-1-, and COX-2-dependent mechanisms in type 2 diabetes

Diabetes. 2013 Jun;62(6):2078-87. doi: 10.2337/db12-1374. Epub 2013 Jan 24.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Benzamides / pharmacology
  • Cells, Cultured
  • Cyclohexanones / pharmacology
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Male
  • Mice
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases / genetics
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Sp1 Transcription Factor / genetics
  • Sp1 Transcription Factor / metabolism*


  • Benzamides
  • Cyclohexanones
  • NF-kappa B
  • Sp1 Transcription Factor
  • dehydroxymethylepoxyquinomicin
  • Cyclooxygenase 2
  • Parp1 protein, mouse
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases