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Enhanced NF-κB Activity Impairs Vascular Function Through PARP-1–, SP-1–, and COX-2–Dependent Mechanisms in Type 2 Diabetes

Authors
 Modar Kassan  ;  Soo-Kyoung Choi  ;  Maria Galán  ;  Alexander Bishop  ;  Kazuo Umezawa  ;  Mohamed Trebak  ;  Souad Belmadani  ;  Khalid Matrougui 
Citation
 DIABETES, Vol.62(6) : 2078-2087, 2013 
Journal Title
 DIABETES 
ISSN
 0012-1797 
Issue Date
2013
MeSH
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*
Keywords
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*
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 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.
Files in This Item:
T201305856.pdf Download
DOI
10.2337/db12-1374
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Physiology (생리학교실) > 1. Journal Papers
Yonsei Authors
Choi, Soo Kyoung(최수경) ORCID logo https://orcid.org/0000-0002-7115-6358
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/89262
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