Document Detail

Enhanced NF-κB activity impairs vascular function through PARP-1-, SP-1-, and COX-2-dependent mechanisms in type 2 diabetes.
MedLine Citation:
PMID:  23349490     Owner:  NLM     Status:  MEDLINE    
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.
Modar Kassan; Soo-Kyoung Choi; Maria Galán; Alexander Bishop; Kazuo Umezawa; Mohamed Trebak; Souad Belmadani; Khalid Matrougui
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-01-24
Journal Detail:
Title:  Diabetes     Volume:  62     ISSN:  1939-327X     ISO Abbreviation:  Diabetes     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-05-24     Completed Date:  2013-08-02     Revised Date:  2013-12-06    
Medline Journal Info:
Nlm Unique ID:  0372763     Medline TA:  Diabetes     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2078-87     Citation Subset:  AIM; IM    
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MeSH Terms
Benzamides / pharmacology
Cells, Cultured
Cyclohexanones / pharmacology
Cyclooxygenase 2 / genetics,  metabolism*
Diabetes Mellitus, Type 2 / genetics,  metabolism*
Endothelial Cells / drug effects,  metabolism
NF-kappa B / antagonists & inhibitors,  metabolism*
Poly(ADP-ribose) Polymerases / genetics,  metabolism*
Real-Time Polymerase Chain Reaction
Sp1 Transcription Factor / genetics,  metabolism*
Grant Support
Reg. No./Substance:
0/Benzamides; 0/Cyclohexanones; 0/NF-kappa B; 0/Sp1 Transcription Factor; 0/dehydroxymethylepoxyquinomicin; EC 2; EC Polymerases; EC, mouse

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