Determinants of endothelial function in patients with COPD

Clarenbach, Christian F.; Senn, Oliver; Sievi, Noriane A.; Camen, Giovanni; Gestel, Arnoldus J.R. van; Rossi, Valentina A.; Puhan, Milo A.; Thurnheer, Robert; Russi, Erich W.; Kohler, Malcolm

doi:10.1183/09031936.00144612

Cited by 101 publications

(102 citation statements)

References 39 publications

(43 reference statements)

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“…Prior studies that have investigated the relationship between airflow limitation and endothelial function, however, have produced inconsistent results (6)(7)(8)(9)(10)(11)30). Specifically, a study that used the gold standard method to assess endothelial function (invasive measurement of forearm vasoreactivity to intraarterial infusion of vasodilators) did not identify an association between airflow limitation and endothelial function (30).…”

Section: Discussionmentioning

confidence: 92%

“…Specifically, a study that used the gold standard method to assess endothelial function (invasive measurement of forearm vasoreactivity to intraarterial infusion of vasodilators) did not identify an association between airflow limitation and endothelial function (30). In contrast, others have reported statistically significant associations between airflow limitation and endothelial function, although with large differences in effect size (6)(7)(8)(9)(10)(11). For example, there was a greater than 10-fold difference in the magnitude of change in endothelial function per unit change in FEV 1 between two studies (b = 0.22 vs. 0.019; both P , 0.05) (6,10).…”

Section: Discussionmentioning

confidence: 99%

“…Prior studies have examined the relationship between expiratory airflow and endothelial dysfunction but have produced inconsistent results (6)(7)(8)(9)(10)(11). Because these studies did not assess atherosclerosis per se, it remains unknown if endothelial dysfunction mediates the association between FEV 1 and atherosclerosis.…”

mentioning

confidence: 99%

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Airflow Limitation and Endothelial Dysfunction. Unrelated and Independent Predictors of Atherosclerosis

Chandra¹,

Gupta²,

Strollo³

et al. 2016

Am J Respir Crit Care Med

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Rationale: Lower FEV 1 is associated with increased prevalence of atherosclerosis; however, causal mechanisms remain elusive.Objectives: To determine if systemic endothelial dysfunction mediates the association between reduced FEV 1 and increased atherosclerosis.Methods: Brachial artery endothelial function, pulmonary function, coronary artery calcium, and carotid plaque were assessed in 231 Pittsburgh SCCOR (Specialized Centers for Clinically Oriented Research) study participants; peripheral arterial endothelial function, pulmonary function, and coronary artery calcium were assessed in 328 HeartSCORE (Heart Strategies Concentrating on Risk Evaluation) study participants.Measurements and Main Results: Lower FEV 1 was independently associated with increased atherosclerosis in both cohorts (per 25% lower % predicted FEV 1 : odds ratio [OR], 1.76; 95% confidence interval [CI], 1.30-2.40; P , 0.001 for carotid plaque in SCCOR participants) (per 25% lower % predicted FEV 1 : OR, 1.35; 95% CI, 1.02-1.77; P = 0.03 for coronary artery calcium in HeartSCORE participants). Similarly, reduced endothelial function was independently associated with increased atherosclerosis in both cohorts (per SD lower endothelial function: OR, 1.30; 95% CI, 1.01-1.67; P = 0.04 for carotid plaque in SCCOR participants) (per SD lower endothelial function: OR, 1.38; 95% CI, 1.09-1.76; P = 0.008 and OR, 1.41; 95% CI, 1.07-1.86; P = 0.01 for coronary artery calcium in SCCOR and HeartSCORE participants, respectively). However, there was no association between endothelial dysfunction and FEV 1 , FEV 1 /FVC, low-attenuation area/visual emphysema, and diffusing capacity in SCCOR participants, and between endothelial dysfunction and FEV 1 or FEV 1 /FVC in HeartSCORE participants (all P . 0.05). Adjusting the association between FEV 1 and atherosclerosis for endothelial dysfunction had no impact.Conclusions: Endothelial dysfunction does not mediate the association between airflow limitation and atherosclerosis. Instead, airflow limitation and endothelial dysfunction seem to be unrelated and mutually independent predictors of atherosclerosis.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Airflow Limitation and Endothelial Dysfunction. Unrelated and Independent Predictors of Atherosclerosis

Chandra¹,

Gupta²,

Strollo³

et al. 2016

Am J Respir Crit Care Med

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“…Moreover, HPAEC are of further interest since endothelial dysfunction in smokers is well recognized [26,27] and might contribute to altered inflammatory signaling. Since no effect on the expression levels of miR-223 has been observed in stimulation experiments using smooth muscle and bronchial epithelial cells, a cell-type specific effect of miR-223 induction upon cytokine stimulation cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-223 controls the expression of histone deacetylase 2: a novel axis in COPD

et al. 2016

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Reduced activity of histone deacetylase 2 (HDAC2) has been described in patients with chronic obstructive pulmonary disease (COPD), but the mechanisms resulting in decreased expression of this important epigenetic modifier remain unknown. Here, we employed several in vitro experiments to address the role of microRNAs (miRNAs) on the regulation of HDAC2 in endothelial cells. Manipulation of miRNA levels in human pulmonary artery endothelial cells (HPAEC) was achieved by using electroporation with anti-miRNAs and miRNA mimics. Target prediction software identified miR-223 as a potential repressor of HDAC2. In subsequent stimulation experiments using inflammatory cytokines known to be increased in patients with COPD, miR-223 was found to be significantly induced. Functional analysis demonstrated that overexpression of miR-223 decreased HDAC2 expression and activity in HPAEC. Conversely, HDAC2 expression and activity was preserved in anti-miR-223-treated cells. Direct miRNAtarget interaction was confirmed by reporter gene assay. In a next step, reduced expression of HDAC2 was found to increase the levels of the chemokine fractalkine (CX3CL1). In vivo studies confirmed elevated expression levels of miR-223 in mice exposed to cigarette smoke and in emphysematous lung tissue from LPS-treated mice. Moreover, a significant inverse correlation of miR-223 and HDAC2 expression was found in two independent cohorts of COPD patients. These data emphasize that miR-223, the most prevalent miRNA in COPD, controls expression and activity of HDAC2 in pulmonary cells, which, in turn, might alter the expression profile of chemokines. This pathway provides a novel pathogenic link between dysregulated miRNA expression and epigenetic activity in COPD. KEY MESSAGES: Histone deacetylase 2 is directly targeted by miR-223. Levels of miR-223 are induced by interleukin-1 and tumor necrosis factor-. miR-223 controls the expression of fractalkine by targeting histone deacetylase 2. miR-223 levels are increased in COPD mouse models. miR-223 levels inversely correlate with HDAC2 expression in COPD patients. AbstractReduced activity of Histone Deacetylase 2 (HDAC2) has been described in patients with chronic obstructive pulmonary disease (COPD) but the mechanisms resulting in decreased expression of this important epigenetic modifier remain unknown. Here we employed several in vitro experiments to address the role of microRNAs (miRNAs) on the regulation of HDAC2 in endothelial cells. Manipulation of miRNA levels in human pulmonary artery endothelial cells (HPAEC) was achieved by using electroporation with anti-miRNAs and miRNA mimics.Target prediction software identified miR-223 as a potential repressor of HDAC2. In subsequent stimulation experiments using inflammatory cytokines known to be increased in patients with COPD miR-223 was found to be significantly induced. Functional analysis demonstrated that overexpression of miR-223 decreased HDAC2 expression and activity in HPAEC. Conversely, HDAC2 expression and activity was preserved i...

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“…Endothelial damage may actively contribute to the pathogenesis of COPD (Barr 2011). Hence, it may mechanistically explain the high rate of comorbidity between COPD and CVD (Clarenbach et al 2013). Increased concentrations of circulating endothelial-derived EV are thought to both result from and promote endothelial dysfunction (Sabatier et al 2009).…”

Section: Endothelial Dysfunctionmentioning

confidence: 99%

Extracellular vesicles released in response to respiratory exposures: implications for chronic disease

Benedikter

Wouters

Savelkoul

et al. 2018

Journal of Toxicology and Environmental Health, Part B

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Extracellular vesicles (EV) are secreted signaling entities that enhance various pathological processes when released in response to cellular stresses. Respiratory exposures such as cigarette smoke and air pollution exert cellular stresses and are associated with an increased risk of several chronic diseases. The aim of this review was to examine the evidence that modifications in EV contribute to respiratory exposure-associated diseases. Publications were searched using PubMed and Google Scholar with the search terms (cigarette smoke OR tobacco smoke OR air pollution OR particulate matter) AND (extracellular vesicles OR exosomes OR microvesicles OR microparticles OR ectosomes). All original research articles were included and reviewed. Fifty articles were identified, most of which investigated the effect of respiratory exposures on EV release in vitro (25) and/or on circulating EV in human plasma (24). The majority of studies based their main observations on the relatively insensitive scatter-based flow cytometry of EV (29). EV induced by respiratory exposures were found to modulate inflammation (19), thrombosis (13), endothelial dysfunction (11), tissue remodeling (6), and angiogenesis (3). By influencing these processes, EV may play a key role in the development of cardiovascular diseases and chronic obstructive pulmonary disease and possibly lung cancer and allergic asthma. The current findings warrant additional research with improved methodologies to evaluate the contribution of respiratory exposure-induced EV to disease etiology, as well as their potential as biomarkers of exposure or risk and as novel targets for preventive or therapeutic strategies.

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Determinants of endothelial function in patients with COPD

Cited by 101 publications

References 39 publications

Airflow Limitation and Endothelial Dysfunction. Unrelated and Independent Predictors of Atherosclerosis

Airflow Limitation and Endothelial Dysfunction. Unrelated and Independent Predictors of Atherosclerosis

MicroRNA-223 controls the expression of histone deacetylase 2: a novel axis in COPD

Extracellular vesicles released in response to respiratory exposures: implications for chronic disease

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