JNK and NF‑κB signaling pathways are involved in cytokine changes in patients with congenital heart disease prior to and after transcatheter closure

Abstract

Congenital heart disease (CHD) is a problem in the structure of the heart that is present at birth. Due to advances in interventional cardiology, CHD may currently be without surgery. The present study aimed to explore the molecular mechanism underlying CHD. A total of 200 cases of CHD treated by transcatheter closure as well as 200 controls were retrospectively assessed. Serum cytokines prior to and after treatment were assessed by reverse-transcription quantitative polymerase chain reaction analysis. Furthermore, the levels of proteins associated with c-Jun N-terminal kinase (JNK) and nuclear factor (NF)-κB were assessed by western blot analysis and immunohistochemistry. Furthermore, an animal model of CHD in young pigs was successfully constructed and treated with inhibitors of JNK and/or NF-κB to investigate the roles of these pathways in CHD. The results revealed that tumor necrosis factor-α, interleukin (IL)-6 and IL-8 were significantly elevated in the experimental group following transcatheter closure treatment, compared with those in the healthy control group, and the serum levels of the anti-inflammatory cytokine IL-10 were significantly reduced. Phosphorylated c-Jun and p65 levels in the experimental group were notably higher in the experimental group compared with the control group, but were restored to normal levels following transcatheter closure treatment. Similar results were also obtained in the pig model. The results of the present study suggested that the CHD-associated changes in cytokines, as well as their recovery following transcatheter closure treatment were associated with the JNK and NF-κB signaling pathways. The present study may provide further understanding of the underlying molecular mechanisms in CHD and propose a potential novel target for the treatment of CHD.

Chromosomal microarray analysis in fetuses with an isolated congenital heart defect: A retrospective, nationwide, multicenter study in France

“…When considering VUS, we identified three candidate genes: MAPK8 , PDE1 , and ITGAE . It has been suggested that MAPK8 has a role in the pathogenesis of CHD . There is evidence from animal studies to suggest that PDE1 has important roles in cardiac defects such as hypertrophy and heart failure.…”

“…It has been suggested that MAPK8 has a role in the pathogenesis of CHD. 21 There is evidence from animal studies to suggest that PDE1 has important roles in cardiac defects such as hypertrophy and heart failure. The use of phosphodiesterase inhibitors in the treatment of heart failure has been considered.…”

Mature miR-99a Upregulation in the Amniotic Fluid Samples from Female Fetus Down Syndrome Pregnancies: A Pilot Study

“…Aside the systemic increase in serum pro-inflamatory cytokines, an increase in the myocardial synthesis of pro-inflammatory cytokines (IL-1b, IL-6, TNF-α), but also of IL-10 (predicted to be targeted by miR-99a), has been reported in euploid children with congenital cardiac defects, presumably an effect of pressure overload and correlate with serum levels [63]. Although most of the data point towards a hemodynamic overload of the DS hearts with septal defects as the cause of these changes, recent research has identified two major signaling hubs, JNK and NF-kB able to transduce cytokine signaling in the vertebrate myocardium and having a significant ethiopathogenic potential in children with congenital heart defects [64]. Experimental alteration of NF-kB in the cardiac primordium significantly alters the development of the outflow tract (the transient embryonic structure that connects the aortic sac with the ventricles and whose dismorphogenesis leads to conotruncal congenital heart defects) [65,66].…”

From heart to gut: Exploring the gut microbiome in congenital heart disease

“…CHD patients have shown the presence of circulating markers, primarily cytokines. Fan et al reported the observation of immune activation in patients with CHD, which was evident through an elevation in inflammatory cytokines and a reduction in anti‐inflammatory cytokines [ 66 ]. These cytokine levels returned to normal following transcatheter CHD treatment [ 66 ].…”