Diabetes Journal: Enhanced NF-κB Activity Impairs Vascular Function Through PARP-1–, SP-1–, and COX-2–Dependent Mechanisms in Type 2 Diabetes
Modar Kassan1,2, Soo-Kyoung Choi1, Maria Galán1,2, Alexander Bishop3, Kazuo Umezawa4, Mohamed Trebak5, Souad Belmadani2⇑ , and Khalid Matrougui1,2⇑
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. The 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, the 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.
Diabetes-induced vascular dysfunction is a major clinical problem that is responsible for morbidity and predisposes patients to a variety of cardiovascular diseases (1,2). Vascular endothelial and smooth muscle cell dysfunction are early events in diabetes, characterized by impaired nitric oxide (NO) pathway signaling and potentiation of pressure-induced myogenic tone (3–6). The loss of vascular endothelial NO bioavailability in diabetes results in vasospasm, platelet aggregation, leukocyte adhesion, vascular smooth muscle proliferation, and induction and progression of atherosclerosis (7–9) associated with increases in activity of the proinflammatory transcription factor nuclear factor-κB (NF-κB) (7). The activation of the NF-κB pathway regulates gene expression of cytokines and chemotactic and matrix proteins and induces cell proliferation resulting in the induction and progression of vascular disease (10).
It has been shown that hyperglycemia induces cyclooxygenase (COX)-2 expression through the NF-κB pathway (11). This concept is supported by previous studies showing that COX-2 induction is primarily mediated through the activation of the NF-κB pathway (12,13). It has been reported that NF-κB subunits interact with poly(ADP-ribose) polymerase (PARP)-1 in the nucleus and then both bind to DNA to modulate gene expression (14). Recently, we have demonstrated that PARP-1 activity is enhanced in the vasculature in type 2 diabetes and is involved in the impairment of vascular function (15). It also has been shown that NF-κB regulates inflammatory cytokines through the transcription factor Sp-1 (16,17). Thus, the role and mechanism of NF-κB in vascular dysfunction in type 2 diabetes are important questions that remain unanswered. Therefore, in this study, we determined whether enhanced NF-κB activity impairs vascular function in type 2 diabetes by PARP-1–,Sp-1–, and COX-2–dependent mechanisms and confirmed that the effect of NF-κB is not specific to one vascular bed by including coronary and mesenteric resistance arteries (MRAs).
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