DNA hypermethylation of the NOX5 gene in fetal ventricular septal defect

Abstract

Abstract. Ventricular septal defect (VSD) is the most comon form of congenital heart disease (CHD). DNA hypermethylation analysis may provide an insight into the molecular features and pathogenesis of this heart disease. Although aberrant DNA hypermethylation is implicated in the pathophysiology of this heart disease, only a limited number of genes are known to be epigenetically altered in VSD. We previously identified regulation of the NOX5 gene by hypermethylation in VSD fetuses by promoter methylation microarrays. This study was designed to detect the expression of NOX5 mRNA in VSD and normal fetuses. We also verified the results of promoter methylation microarrays by methylation-specific PCR. DNA extraction and nested methylation-specific PCR were performed on myocardial tissue samples from 21 VSD and 15 normal fetuses. The primers specific for methylated vs. unmethylated DNA were designed and amplified by nested PCR. The products were visualized on agarose gel. Hypermethylation of the NOX5 promoter was more frequent in VSD fetuses (66.67%) than in normal fetuses (20%). There was a significant concordance between NOX5 methylation and a decrease in its mRNA expression. Taken together, our results demonstrate that hypermethylation of the NOX5 gene may be involved in the pathogenesis of VSD.

DNA methylation profiles in preeclampsia and healthy control placentas

“…ROS, derived by the NOX family, have roles in cell proliferation, transformation, differentiation, and apoptosis. NOX5 has been shown to be highly expressed during embryonic development, and hypermethylation of the NOX5 promoter region has been associated with congenital heart disease in human fetuses (39). Hypermethylation of NOX5 leads to transcriptional silencing (39) and a reduction in the production of ROS.…”

The role of epigenetic changes in preeclampsia

“…NOX5 is the member of the NADPH oxidase family and is a basic source of reactive oxygen species (ROS). ROS have different roles, including transformation, apoptosis, proliferation and differentiation, and hypermethylation of NOX5 gene is associated with pregnancy disorders . Yeung et al also demonstrated hypermethylation of CpG sites of NOX5 in PE.…”

Enzymatic regulation and functional relevance of NOX5

“…Epigenetics may have a more profound role in the regulation of NOX5 expression in different cells types. The expression of NOX5 has been shown to be negatively influenced by DNA methylation 49 which may account for cell-specific regulation and changes in expression in disease states. The relatively ratio of different splice variants of NOX5 appears to vary with NOX5α(V1) the predominant form in blood vessels 41 , NOX5βand δ(V2 and V3) in endothelial cells 22 , NOX5α-γ(V1-V4) in smooth muscle cells 22 , NOX5β(V2) in podocytes 11 and NOX5ε(V6) in Barrett's esophageal adenocarcinoma cells 46 .…”