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Lung neprilysin activity and expression are decreased in humans with COPD and pulmonary vascular remodeling
Author(s) -
Wick Marilee J,,
Barr Erica J.,
Wehling Carol A.,
Cool Carlyne D.,
Zamora Marty,
Miller York E.,
Hersh Louis B.,
Voelkel Norbert F.,
Dempsey Edward C.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.770.3
Subject(s) - copd , neprilysin , lung , vascular remodelling in the embryo , medicine , hypoxia (environmental) , pulmonary hypertension , pulmonary artery , cardiology , endocrinology , pathology , biology , chemistry , enzyme , biochemistry , organic chemistry , oxygen
Pulmonary vascular remodeling and pulmonary hypertension (PHTN) are common in chronic obstructive pulmonary disease (COPD). Hypoxia, cigarette smoke, oxidant stress, and other factors may contribute to COPD, and may also decrease the activity or expression of the cell surface peptidase, Neprilysin (NEP). Recent studies with mice actually suggest that NEP may protect the lung vasculature from hypoxic PHTN, but NEP's importance in human pulmonary vascular disease is unknown. We hypothesized that NEP activity and/or expression is selectively reduced in humans with COPD and pulmonary vascular remodeling. Fixed sections were scored for pulmonary vascular remodeling in a blinded fashion. NEP activity and protein expression in lung lysates were reduced by 70% in COPD samples (n=14) vs control. In contrast, levels of dipeptidyl peptidase IV, another relevant peptidase, did not change. In order to understand the mechanisms responsible for these changes in NEP, human pulmonary artery SMCs were exposed to hypoxia, cigarette smoke extract, or ROS. Large decreases were measured in NEP activity and protein levels, while more modest decreases in NEP mRNA were noted, suggesting several levels of control. We conclude that decreased NEP may predispose to pulmonary vascular remodeling in COPD, and therapeutic strategies to increase NEP in the lung may prevent or attenuate some pulmonary vascular disorders.