Enhanced NF-κB Activity Impairs Vascular Function Through PARP-1–, SP-1–, and COX-2–Dependent Mechanisms in Type 2 Diabetes
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説明
<jats:p>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.</jats:p>
収録刊行物
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- Diabetes
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Diabetes 62 2078-2087, 2013-05-17
American Diabetes Association
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キーワード
- Type 2/genetics
- Male
- Sp1 Transcription Factor
- Cells
- Poly(ADP-ribose) Polymerases/metabolism*
- Poly (ADP-Ribose) Polymerase-1
- Endothelial Cells/metabolism
- Real-Time Polymerase Chain Reaction
- Cyclooxygenase 2/genetics
- Sp1 Transcription Factor/genetics
- Mice
- Diabetes Mellitus
- Type 2/metabolism*
- Animals
- Cells, Cultured
- Endothelial Cells/drug effects
- Original Research
- Cultured
- Poly(ADP-ribose) Polymerases/genetics
- Cyclohexanones
- NF-kappa B
- Benzamides/pharmacology
- Endothelial Cells
- NF-kappa B/metabolism*
- NF-kappa B/antagonists & inhibitors
- Cyclohexanones/pharmacology
- Diabetes Mellitus, Type 2
- Cyclooxygenase 2
- Benzamides
- Sp1 Transcription Factor/metabolism*
- Poly(ADP-ribose) Polymerases
- Cyclooxygenase 2/metabolism*