Decreased Neprilysin and Pulmonary Vascular Remodeling in Chronic Obstructive Pulmonary Disease

Abstract

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-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. 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 5 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 H 2 O 2 , 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 H 2 O 2 , 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.Keywords: pulmonary hypertension; smooth muscle cell; smoking; oxidative stress; protein degradation Chronic obstructive pulmonary disease (COPD) is a leading cause of death; cigarette smoking is its number one risk factor (1). Pulmonary vascular remodeling, characterized by thickening, muscularization, and rarification of the distal vasculature (2-4), complicates COPD by contributing to pulmonary hypertension (PHTN) (3, 5). Many patients with COPD have mild PHTN at rest (6-8); however, the prevalence of exerciseinduced PHTN, which also may lead to right-sided heart failure in COPD (9), is much higher (. 91% [6,10]).COPD-associated PHTN is likely caused by initial injury of the pulmonary vascular endothelium by cigarette smoke (CS) (4), followed by inflammation and hypoxia, all of which may involve oxidant mechanisms (11,12). Factors that may contribute to variable susceptibility to COPD-associated PHTN, including interleukin-6 (IL-6) and the serotonin transporter (5HTT) (6,10,13,14), have been extensively investigated.Neprilysin (NEP, CD10) is a transmembrane ...

Neprilysin Regulates Pulmonary Artery Smooth Muscle Cell Phenotype Through a Platelet-Derived Growth Factor Receptor–Dependent Mechanism

“…This is consistent with our recent observations that NEP null mice have enhanced hypoxia-induced pulmonary vascular remodeling and expression of NEP is decreased in lungs of patients with chronic pulmonary obstructive disease (COPD) and pulmonary vascular remodeling 28, 8 . We also show that ET A antagonist effects may be mediated at least in part by inhibition of PDGFR responses.…”

Neprilysins: An Evolutionarily Conserved Family of Metalloproteases That Play Important Roles in Reproduction in Drosophila

“…In mammals, seven members of this family have been identified, of which neprilysin (NEP) and endothelin converting enzyme (ECE) are the best studied. These proteins have been implicated in various diseases including cardiovascular disease (Segura and Ruilope 2011;Wick et al 2011), Alzheimer's disease (Mulder et al 2012;Klein et al 2013), inflammation and inflammatory disorders (Wong et al 2011), and cancer (Smollich et al 2007;Maguer-Satta et al 2011).…”

Neprilysin Inhibitors as a New Approach in the Treatment of Right Heart Failure in the Course of Chronic Obstructive Pulmonary Disease

“…Decreased expression of NEP or lack of this enzyme have been associated with pulmonary vascular remodelling in response to chronic hypoxia [19]. In addition, NEP expression was reduced in the lungs of COPD patients [20], which may possibly exacerbate pulmonary vascular remodeling in COPD [20]. COPD often leads to PH [21,22], which is connected with chronic hypoxia, noxious effects of tobacco smoke, free radicals and inflammatory mediators, such as IL-6 [21][22][23][24].…”

“…COPD often leads to PH [21,22], which is connected with chronic hypoxia, noxious effects of tobacco smoke, free radicals and inflammatory mediators, such as IL-6 [21][22][23][24]. In the course of PH, pulmonary vascular remodelling arises through proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) [19,20,23,[25][26][27] and endothelial-to-mesenchymal transition (EndoMT) [28]. Ultimately, this hypertension can lead to RHF [22].…”