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

Modar Kassan, Soo Kyoung Choi, Maria Galán, Alexander Bishop, Kazuo Umezawa, Mohamed Trebak, Souad Belmadani, Khalid Matrougui

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2078-2087
Number of pages10
JournalDiabetes
Volume62
Issue number6
DOIs
StatePublished - Jun 1 2013

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Cyclooxygenase 2
Type 2 Diabetes Mellitus
Blood Vessels
Endothelium
Arteries
Phosphorylation
Lentivirus
Mesenteric Arteries
Arterioles
Poly (ADP-Ribose) Polymerase-1
Knockout Mice
Small Interfering RNA
Blood Glucose
Down-Regulation
Body Weight
RNA
Pressure

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Kassan, Modar ; Choi, Soo Kyoung ; Galán, Maria ; Bishop, Alexander ; Umezawa, Kazuo ; Trebak, Mohamed ; Belmadani, Souad ; Matrougui, Khalid. / Enhanced NF-κB activity impairs vascular function through PARP-1-, SP-1-, and COX-2-dependent mechanisms in type 2 diabetes. In: Diabetes. 2013 ; Vol. 62, No. 6. pp. 2078-2087.
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title = "Enhanced NF-κB activity impairs vascular function through PARP-1-, SP-1-, and COX-2-dependent mechanisms in type 2 diabetes",
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.",
author = "Modar Kassan and Choi, {Soo Kyoung} and Maria Gal{\'a}n and Alexander Bishop and Kazuo Umezawa and Mohamed Trebak and Souad Belmadani and Khalid Matrougui",
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Kassan, M, Choi, SK, Galán, M, Bishop, A, Umezawa, K, Trebak, M, Belmadani, S & Matrougui, K 2013, 'Enhanced NF-κB activity impairs vascular function through PARP-1-, SP-1-, and COX-2-dependent mechanisms in type 2 diabetes', Diabetes, vol. 62, no. 6, pp. 2078-2087. https://doi.org/10.2337/db12-1374

Enhanced NF-κB activity impairs vascular function through PARP-1-, SP-1-, and COX-2-dependent mechanisms in type 2 diabetes. / Kassan, Modar; Choi, Soo Kyoung; Galán, Maria; Bishop, Alexander; Umezawa, Kazuo; Trebak, Mohamed; Belmadani, Souad; Matrougui, Khalid.

In: Diabetes, Vol. 62, No. 6, 01.06.2013, p. 2078-2087.

Research output: Contribution to journalArticle

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T1 - Enhanced NF-κB activity impairs vascular function through PARP-1-, SP-1-, and COX-2-dependent mechanisms in type 2 diabetes

AU - Kassan, Modar

AU - Choi, Soo Kyoung

AU - Galán, Maria

AU - Bishop, Alexander

AU - Umezawa, Kazuo

AU - Trebak, Mohamed

AU - Belmadani, Souad

AU - Matrougui, Khalid

PY - 2013/6/1

Y1 - 2013/6/1

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AB - 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.

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