NOX4 expression and distal arteriolar remodeling correlate with pulmonary hypertension in COPD

Abstract

BackgroundPulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD) is suggested as the consequence of emphysematous destruction of vascular bed and hypoxia of pulmonary microenvironment, mechanisms underpinning its pathogenesis however remain elusive. The dysregulated expression of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidases and superoxide generation by pulmonary vasculatures have significant implications in the hypoxia-induced PH.MethodsIn this study, the involvement of NADPH oxidase subunit 4 (NOX4) in pulmonary arteriolar remodeling of PH in COPD was investigated by ascertaining the morphological alteration of pulmonary arteries and pulmonary blood flow using cardiac magnetic resonance imaging (cMRI), and the expression and correlation of NOX4 with pulmonary vascular remodeling and pulmonary functions in COPD lungs.ResultsResults demonstrated that an augmented expression of NOX4 was correlated with the increased volume of pulmonary vascular wall in COPD lung. While the volume of distal pulmonary arteries was inversely correlated with pulmonary functions, despite it was positively associated with the main pulmonary artery distensibility, right ventricular myocardial mass end-systolic and right ventricular myocardial mass end-diastolic in COPD. In addition, an increased malondialdehyde and a decreased superoxide dismutase were observed in sera of COPD patients. Mechanistically, the abundance of NOX4 and production of reactive oxygen species (ROS) in pulmonary artery smooth muscle cells could be dynamically induced by transforming growth factor-beta (TGF-β), which in turn led pulmonary arteriolar remodeling in COPD lungs.ConclusionThese results suggest that the NOX4-derived ROS production may play a key role in the development of PH in COPD by promoting distal pulmonary vascular remodeling.

Vasoconstrictor Mechanisms in Chronic Hypoxia-Induced Pulmonary Hypertension: Role of Oxidant Signaling

“…Although biochemical evidence suggests H 2 O 2 is the major product of NOX4 [ 99 , 100 , 101 ], NOX4-dependent generation of both O 2 .− [ 82 , 97 ] and H 2 O 2 [ 82 , 95 , 96 ] has been observed in the pulmonary vasculature. NOX4 expression in PAs from COPD patients [ 102 ] and CH mice [ 90 ] is higher than those from controls. NOX4 promotes proliferation of human PASMCs [ 90 ] and correlates with the severity of PA remodeling in COPD patients [ 102 ], suggesting a pathological role for NOX4 in CH-induced PH.…”

“…NOX4 expression in PAs from COPD patients [ 102 ] and CH mice [ 90 ] is higher than those from controls. NOX4 promotes proliferation of human PASMCs [ 90 ] and correlates with the severity of PA remodeling in COPD patients [ 102 ], suggesting a pathological role for NOX4 in CH-induced PH. In comparison to wild-type (WT) mice, Hood et al [ 98 ] demonstrated that RVSP is diminished in NOX4 knockout (KO) mice following CH (10% O 2 for 15 days).…”

Downregulation of epithelial DUOX1 in chronic obstructive pulmonary disease

“…While all seven NOX enzymes are all expressed in various cell types within the lung, relatively little is known with respect to their potential role in COPD pathology. Several reports indicate that NOX4 is upregulated in airway smooth muscle of COPD patients and correlates with disease severity (17,18). NOX2, primarily expressed in cells of the innate immune system, also appears to be increased in COPD, and some studies suggest that NOX2 contributes to experimental emphysema, although contrasting findings were reported as well and NOX2-deficiency may even promote spontaneous emphysema (19)(20)(21).…”

New therapeutic targets for the prevention of infectious acute exacerbations of COPD: role of epithelial adhesion molecules and inflammatory pathways

“…and DUOX2 with airflow obstruction; NOX1 with airway inflammation (neutrophils and eosinophils) [306]. NOX4 may also be involved in promoting airway smooth muscle remodelling in the small airways of COPD [311,312] and is readily induced by cigarette smoke [307]. Thus, isoform differences may impact effectiveness of new therapies targeting NOXgenerated ROS, particularly as drugs like apocynin are isoform-specific [308].…”