Nuclear factor kappa B inhibition improves conductance artery function in type 2 diabetic mice

Abstract

Background We previously reported that enhanced nuclear factor kappa B (NFκB) activity is responsible for resistance arteries dysfunction in type 2 diabetic mice. Methods In this study we aimed to determine whether augmented NFkB activity also impairs conductance artery (thoracic aorta) function in type 2 diabetic mice. We treated type 2 diabetic (db−/db−) and control (db−/db+) mice with two NFκB inhibitors (DHMEQ, 6 mg/kg, twice a week and IKK-NBD peptide, 500 μg/kg/day) for four weeks. Results As expected, the NFκB inhibition did not affect blood glucose level and body weight. Thoracic aorta vascular endothelium-dependent relaxation (EDR), determined by the wire myograph, was impaired in diabetic mice compared to control, and was significantly improved after NFκB inhibition. Interestingly, thoracic EDR was also rescued in db−/db-p50NFκB−/− and db−/db-PARP-1−/− double knockout mice compared to db−/db− mice. Similarly, the acute in vitro down regulation of NFκB-p65 using p65 shRNA lentiviral particles in arteries from db−/db− mice also improved thoracic aorta EDR. Western blot analysis showed that the p65NFκB phosphorylation, cleaved PARP-1 and COX-2 expression were increased in thoracic aorta from diabetic mice, which were restored after NFκB inhibition and in db−/db-p-50NFκB−/− and db−/db-PARP-1−/− mice. Conclusions The present results indicate that in male type 2 diabetic mice, the augmented NFκB activity also impairs conductance artery function through PARP-1 and COX-2-dependent mechanisms.

The dual targeting of EGFR and ErbB2 with the inhibitor Lapatinib corrects high glucose-induced apoptosis and vascular dysfunction by opposing multiple diabetes-induced signaling changes

“…These data and the fact that the NF-kB inhibitor BAY corrected the abnormal vascular reactivity to NE in the MVB (Figure 8) as well as high glucose-induced apoptosis in VSMC (Figure 9) supports the notion that increased EGFR-ErbB2 activity in the vasculature of type 1 diabetes leads to increased NF-kB activation that ultimately leads to vascular apoptosis and dysfunction. Our findings are also supported by a recent report in coronary arteries isolated from a mouse model of type 2 diabetes that showed acute pharmacological blockade of EGFR tyrosine kinase by AG1478 partly prevented the diabetes-induced phosphorylation of p65 subunit of NF-kB [37]. Thus, taken together with our present study, these data suggest that NF-kB is a downstream effector of EGFR-ErbB2 receptors in the vasculature of both type 1 and 2 diabetes.…”

“…Thus, taken together with our present study, these data suggest that NF-kB is a downstream effector of EGFR-ErbB2 receptors in the vasculature of both type 1 and 2 diabetes. In type 2 diabetes, elevated activity of NF-kB is thought to impair vascular function via PARP-1-, SP1-and COX-2-dependent pathways [37]; whether this is also the case in type 1 diabetes is not yet known. Also, our study reveals a novel anti-inflammatory action of Lapatinib in that it can inhibit NF-kB in the diabetic vasculature.…”

Macro‐ and microvascular endothelial dysfunction in diabetes

“…In addition, oxygen radicals, such as superoxide anions and hydroxyl radicals, can contract vascular smooth muscle cells, thus acting as an EDCF . In diabetic animals, EDCF‐mediated contractions are augmented in conduit arteries, including the aorta and femoral and renal arteries, as well as in mesenteric resistance arteries …”

The Role of Epidermal Growth Factor Receptor Family of Receptor Tyrosine Kinases in Mediating Diabetes-Induced Cardiovascular Complications

“…Administration of AG1478, a selective EGFR inhibitor, or AG825, a specific ErbB2 inhibitor, or Fasudil, a ROCK inhibitor, or PD98059, an ERK1/2 signaling inhibitor, all attenuated the observed changes associated with diabetes-induced vascular dysfunction ( Akhtar et al, 2013 ) indicating the importance of these effectors in this pathology. Similarly, in a mouse model of T2DM, EGFR inhibition rescued abnormal ROCK activity and restored vascular function ( Kassan et al, 2015b ). Collectively, these results implied that EGFR/ErbB2-ERK1/2-ROCK pathway is an important mediator of diabetes-induced vascular dysfunction.…”

“…In contrast to these studies, in a rat model of TIDM, chronic selective inhibition of PI3K with LY294002 significantly attenuated the development of diabetes-induced abnormal vascular reactivity in the carotid artery ( Yousif et al, 2006 ) implying that that PI3K pathway might also mediate vascular dysfunction. The reasons for this discrepancy are not clear but several reports have now confirmed AKT, and by implication PI3K to which it often coupled, as a downstream player in ErbB receptor-dependent vascular dysfunction in models of diabetes ( Benter et al, 2015 ; Kasan et al, 2015b ; Amin et al, 2011 ). For example, in the diabetic mesenteric vascular bed, hyperglycemia-induced upregulation of Akt signaling was prevented by lapatinib, a dual inhibitor of EGFR and ErbB2 ( Benter et al, 2015 ).…”