TY - JOUR
T1 - Decreased neprilysin and pulmonary vascular remodeling in chronic obstructive pulmonary disease
AU - Wick, Marilee J.
AU - Buesing, Erica J.
AU - Wehling, Carol A.
AU - Loomis, Zoe L.
AU - Cool, Carlyne D.
AU - Zamora, Martin R.
AU - Miller, York E.
AU - Colgan, Sean P.
AU - Hersh, Louis B.
AU - Voelkel, Norbert F.
AU - Dempsey, Edward C.
PY - 2011/2/1
Y1 - 2011/2/1
N2 - Rationale: 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-typemice, 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. Objectives: 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 andprotein 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. Measurements and Main 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.
AB - Rationale: 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-typemice, 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. Objectives: 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 andprotein 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. Measurements and Main 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.
KW - Oxidative stress
KW - Protein degradation
KW - Pulmonary hypertension
KW - Smoking
KW - Smooth muscle cell
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U2 - 10.1164/rccm.201002-0154OC
DO - 10.1164/rccm.201002-0154OC
M3 - Article
C2 - 20813891
AN - SCOPUS:79551562936
SN - 1073-449X
VL - 183
SP - 330
EP - 340
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
IS - 3
ER -
