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.

Peptide-based inhibition of IκB kinase/nuclear factor-κB pathway protects against diabetes-associated nephropathy and atherosclerosis in a mouse model of type 1 diabetes

“…We have provided in vivo evidence that NBD peptide dose-dependently attenuates NF-κB activation in the aorta and limits atheroma plaque formation in type 1 diabetic Apoe −/− mice. This finding is in agreement with that of a recently published report showing that NBD improved vascular dysfunction (in terms of myogenic tone and endothelium-dependent relaxation) in coronary and mesenteric resistance arteries from a mouse model of type 2 diabetes [45]. Importantly, we observed that NF-κB inhibition altered plaque composition and inflammation in mouse atherosclerotic lesions without affecting serum lipid levels.…”

Inhibition of endoplasmic reticulum stress improves coronary artery function in type 2 diabetic mice

“…The myogenic response is characterized by vasoconstriction in response to an increase of intraluminal pressure and vasodilatation in response to a decrease in intraluminal pressure and is an intrinsic vascular response that plays an important role in the local regulation of blood flow (Bayliss, 1902). Previous studies have shown that impaired small artery function is attributable to the enhanced myogenic response in diabetic animals (Lagaud et al 2001;Choi et al 2012;Kassan et al 2013). Interestingly, in the present study, we observed an enhanced myogenic response in the coronary arteries of type 2 diabetic mice associated with increased ER stress markers.…”

“…As a result, patients with diabetes have a much higher risk of myocardial infarction (Diabetes Control and Complications Trial Research Group, 1993; UK Prospective Diabetes Study Group, 1998). It has been suggested that various factors, including metabolic factors, advanced glycation end-products and endothelial dysfunction, contribute to diabetes-induced vascular complications (Nogueira-Machado & Chaves, 2008;Kassan et al 2013;Manigrasso et al 2014). Although the link between diabetes and cardiovascular disease is not fully understood, it is considered that potentiation of the pressure-induced myogenic response and impaired endothelium-dependent relaxation are main characteristics of diabetic vascular dysfunction (Cai et al 2005).…”

20-HETE Activates the Transcription of Angiotensin-Converting Enzyme via Nuclear Factor- B Translocation and Promoter Binding

“…The IKK complex and NF-kB have been implicated in a variety of vascular diseases and complications, including obesity (Kassan et al, 2013), renal disease, and hypertension (Cardinale et al, 2012). In animal models, hypertensioninduced renal damage can be attenuated by endothelialspecific cell suppression of NF-kB (Henke et al, 2007).…”