Decreased lung neprilysin gene expression in humans with COPD and pulmonary vascular remodeling

Abstract

Pulmonary vascular remodeling contributes to pulmonary hypertension (PHTN), complicating chronic obstructive pulmonary disease (COPD). Because NEP may be protective against PHTN, it is important to understand mechanisms operative in COPD that cause NEP expression decreases. In addition to decreases of nearly 50% in NEP protein levels, we found that NEP mRNA levels are decreased by 30% in COPD lung; therefore, we focused on DNA damage mechanisms or epigenetic changes to the NEP gene. Lung sections stained for 8-hydroxyguanosine (formed by ROS reaction with guanine) were more heavily stained in COPD than in ‘Control’. However, no differences were found when specific NEP gene damage was studied. Next, we used methylation-specific PCR, methylation sensitive and resistant restriction enzymes, and methyl-binding proteins, to detect DNA methylation, primarily within the CpG island in the promoter region of the NEP gene, but found no differences between COPD and ‘Control’. The possibilities that CpG islands within other parts of the gene, or even within non-CpG islands, may be differentially methylated, are being investigated. Future experiments will address other epigenetic changes (histone modifications and microRNA regulation) to the NEP gene. Our results may suggest new ways to treat and/or prevent pulmonary vascular remodeling and PHTN, as in COPD. Support: NHLBI RO1-HL-078929, RO3-HL-095430, and the VA.