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Downregulation of endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) in a co-culture system with human stimulated X-linked CGD neutrophils

宇都宮朱里広島大学

2020.05.28

概要

Chronic granulomatous disease (CGD) is a rare, heterogenous, and inherited disorder that
affects approximately 1 in 250,000 births [1]. It has been reported that X-linked CGD occurs
in approximately 70% of patients with CGD and is due to the mutation of CYBB encoding
gp91phox, which is located at Xp21.1 [2, 3]. NADPH oxidase activity is diminished in activated leukocytes obtained from these patients, leading to a reductions in reactive oxygen
species (ROS) such as H2O2 and resulting in severe and recurrent bacterial and fungal infections. Among the mutational defects of the NADPH oxidase subunit complex, functional
deficiency of gp91phox is the most common, resulting in X-CGD [4]. It has already been
reported that phagocytes in CGD patients do not generate ROS such as superoxide ions
(O2-) and H2O2 under inflammatory stimulation (e.g., with lipopolysaccharide), whereas
nitric oxide (NO) production by CGD phagocytes has been reported to be increased in
response to a calcium ionophore, A23187, compared with that of phagocytes from healthy
people [5–10].
In 2009, Violi et al. reported that lower oxidative stress and enhanced arterial dilatation
as assessed by flow-mediated dilatation (FMD) testing were detected in X-CGD patients,
reflecting increased bioavailability or higher levels of NO [11–13]. Their findings suggested
that oxidative stress derived from neutrophils may have a pivotal role in modulating endothelial function [14,15]. However, the precise interactions between the NO and ROS produced by neutrophils in particular, and their effects on endothelial function, remain to be
elucidated.
The endothelium is a regulator of vascular tone by releasing relaxing and contracting factors [16]. Among various endothelial-derived relaxing factors, the main species identified is
NO, which is released in response to a variety of stimuli [17]. NO is a strong vasodilator and
functions as a potent signaling molecule in many internal cells, including vascular endothelial
cells [17, 18]. Among the three distinct isoforms of NO synthase (NOS), the relatively small
amounts of NO produced by endothelial NOS (eNOS) are important for cardiovascular
homeostasis, whereas the high NO levels associated with activated inducible NOS (iNOS) are
related to infection and inflammation in vivo [19]. An excessive dose of NO is likely to induce
endothelial damage. In addition, because NO is produced by NOS in several cell types, it can
rapidly undergo a series of reactions with molecules such as oxygen and superoxide anions
that inactivate NO [20]. Among these reactions, NO reacts more rapidly with O2- to form peroxinitrite (ONO2-, which itself is strongly oxidizing) than with O2- to form H2O2 [20]. It has
also been reported that shear stress, which is important for inducing eNOS expression, stimulates increased eNOS (NOS3) transcription via activation of nuclear factor kappa B (NFκB)
and binding of p50/p65 heterodimers to a shear responsive element in the human NOS3 promoter [21].
In addition to NO, endothelin-1 (ET-1) has been considered as an essential molecules in
the process of endothelial toning as well as eNOS [22–24]. There are several reports indicating
that NO has a role in the inhibitory regulation of ET-1 (EDN1) production at the transcription
level in endothelial cells [25–27]. In vascular systems, NOS3 and EDN1 cooperate as a toningmodulator molecules with opposing roles.
In this study, we hypothesized that the gp91phox subunit of NADPH oxidase derived from
neutrophils could have a significant effect on endothelial function. To investigate this potential
effect, we focused on the effect of NO and H2O2 from neutrophils obtained from patients with
X-CGD on the expression of NOS3 and EDN1 mRNA in human umbilical vein endothelial cells
(HUVECs). In addition, we demonstrated that the protein expression of eNOS, ET-1, phosphorylated eNOS at Ser1177 position, total NFκB at p65, and phosphorylated p65 at Ser536. ...

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Downregulation of endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) in a co-culture system with human stimulated X-linked CGD neutrophils

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