Cardiac-specific suppression of NF-κB signaling prevents diabetic cardiomyopathy via inhibition of the renin-angiotensin system

Abstract

Activation of NF-κB signaling in the heart may be protective or deleterious depending on the pathological context. In diabetes, the role of NF-κB in cardiac dysfunction has been investigated using pharmacological approaches that have a limitation of being nonspecific. Furthermore, the specific cellular pathways by which NF-κB modulates heart function in diabetes have not been identified. To address these questions, we used a transgenic mouse line expressing mutated IκB-α in the heart (3M mice), which prevented activation of canonical NF-κB signaling. Diabetes was developed by streptozotocin injections in wild-type (WT) and 3M mice. Diabetic WT mice developed systolic and diastolic cardiac dysfunction by the 12th week, as measured by echocardiography. In contrast, cardiac function was preserved in 3M mice up to 24 wk of diabetes. Diabetes induced an elevation in cardiac oxidative stress in diabetic WT mice but not 3M mice compared with nondiabetic control mice. In diabetic WT mice, an increase in the phospholamban/sarco(endo)plasmic reticulum Ca(2+)-ATPase 2 ratio and decrease in ryanodine receptor expression were observed, whereas diabetic 3M mice showed an opposite effect on these parameters of Ca(2+) handling. Significantly, renin-angiotensin system activity was suppressed in diabetic 3M mice compared with an increase in WT animals. In conclusion, these results demonstrate that inhibition of NF-κB signaling in the heart prevents diabetes-induced cardiac dysfunction through preserved Ca(2+) handling and inhibition of the cardiac renin-angiotensin system.

Mitochondrial Dysfunction in Diabetic Cardiomyopathy: Effect of Mesenchymal Stem Cell with PPAR-γ Agonist or Exendin-4

“…The correlation studies gave evidence of the presence of the negative association between the levels of LVDP and NFKB gene expression in all groups, (P < 0.001). This was in accordance with the work of Thomas et al [45] who reported that prolonged activation of NF-κB was observed in the diabetic cardiomyopathy.…”

Protective effects of resveratrol improve cardiovascular function in rats with diabetes

“…NO is also able to transmit signals and regulate enzymatic activities and immunoregulation, inhibit vascular smooth muscle cell proliferation and platelet adhesion and accumulation, and induce resistance to oxidative damage (28). Capillary endothelial cell eNOS catalyzes the secretion of NO that enters the surrounding cardiac and vascular smooth muscle cells, which protects granular leukocytes and blood platelets (29). In the present study, resveratrol treatment significantly increased the expression of eNOS expression in rats with STZ-DRMI.…”

Silencing of ATP2B1‐AS1 contributes to protection against myocardial infarction in mouse via blocking NFKBIA‐mediated NF‐κB signalling pathway

“…The activation of NF‐κB was triggered by IκBα degradation via phosphorylation by the IκB kinase complex . NF‐κB activation has been found in other different heart diseases, including cardiac hypertrophy, diabetic cardiomyopathy, myocardial infarction, ischaemia‐reperfusion injury and heart failure . The signalling pathways that mediate NF‐κB activation could be divided into canonical pathways (mainly p50‐RelA) and non‐canonical (mainly p52‐RelB) pathways .…”