Decreased neprilysin and pulmonary vascular remodeling in chronic obstructive pulmonary disease.
BACKGROUND
Studies with genetically engineered mice showed that decreased expression of the transmembrane peptidase neprilysin (NEP) increases susceptibility to hypoxic pulmonary vascular remodeling and hypertension; in hypoxic wild-type mice, expression is decreased early in distal pulmonary arteries, where prominent vascular remodeling occurs. Therefore, in humans with smoke- and hypoxia-induced vascular remodeling, as in chronic obstructive pulmonary disease (COPD), pulmonary activity/expression of NEP may likewise be decreased.


OBJECTIVE
To test whether NEP activity and expression are reduced in COPD lungs and pulmonary arterial smooth muscle cells (SMCs) exposed to cigarette smoke extract or hypoxia and begin to investigate mechanisms involved.


METHODS
Control and advanced COPD lung lysates (n = 13-14) were analyzed for NEP activity and protein and mRNA expression. As a control, dipeptidyl peptidase IV activity was analyzed. Lung sections were assessed for vascular remodeling and oxidant damage. Human pulmonary arterial SMCs were exposed to cigarette smoke extract, hypoxia, or H₂O₂, and incubated with antioxidants or lysosomal/proteasomal inhibitors.


RESULTS
COPD lungs demonstrated areas of vascular rarification, distal muscularization, and variable intimal and prominent medial/adventitial thickening. NEP activity was reduced by 76%; NEP protein expression was decreased in alveolar walls and distal vessels; mRNA expression was also decreased. In SMCs exposed to cigarette smoke extract, hypoxia, and H₂O₂, NEP activity and expression were also reduced. Reactive oxygen species inactivated NEP activity; NEP protein degradation appeared to be substantially induced.


CONCLUSIONS
Mechanisms responsible for reduced NEP activity and protein expression include oxidative reactions and protein degradation. Maintaining or increasing lung NEP may protect against pulmonary vascular remodeling in response to chronic smoke and hypoxia.
Wick
Marilee J
MJ
Cardiovascular Pulmonary Research Laboratory, University of Colorado Denver, Aurora, CO 80045, USA. edward.dempsey@ucdenver.edu
Buesing
Erica J
EJ
Wehling
Carol A
CA
Loomis
Zoe L
ZL
Cool
Carlyne D
CD
Zamora
Martin R
MR
Miller
York E
YE
Colgan
Sean P
SP
Hersh
Louis B
LB
Voelkel
Norbert F
NF
Dempsey
Edward C
EC
D000293:Adolescent; D000368:Aged; D056151:Airway Remodeling / Q000502:physiology*; D015153:Blotting, Western; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000737:chemistry / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015260:Neprilysin / Q000032:analysis / Q000502:physiology*; D011650:Pulmonary Alveoli / Q000473:pathology; D011651:Pulmonary Artery / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000473:pathology* / Q000503:physiopathology; D055815:Young Adult
D015260:Neprilysin
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