Introduction
Chronic obstructive pulmonary disease (COPD) is a major incurable global
health burden and is currently the 4th largest cause
of death in the world (WHO, 2018). Approximately 50% of COPD patients
will die from a cardiovascular event (Sin & Man, 2005; TLF, 2017) and
consequently the pathobiological mechanisms linking COPD to
cardiovascular disease are now an area of intensive research. Each puff
of cigarette smoke contains >1016 free
radicals per puff, driving oxidative stress and tissue damage (Bartalis,
Chan & Wooten, 2007) This oxidative stress and inflammation, have been
shown to alter pulmonary blood vessel structure, through driving
vascular remodelling, and promoting arterial stiffness and
atherosclerosis (Sin, Anthonisen, Soriano & Agusti, 2006). Vascular
tone is controlled by vasoactive substances such as NO and
prostaglandins, their secretion which can be maintained by circulating
oxygen levels (Chan & Vanhoutte, 2013). Under hypoxic conditions like
those seen in COPD, dysregulation of this vascular homeostatic balance
occurs, due to oxidative damage to the vascular endothelial cells (VECs)
leading to impaired NO production, thereby promoting endothelial
dysfunction (Chan & Vanhoutte, 2013). NO is a key vasodilator produced
by endothelial nitric oxide synthase (eNOS). Under normal physiological
conditions, increased sheer stress on the vascular endothelium
stimulates mechanosensitive ion channels, triggering a rapid influx of
Ca2+ into the cytoplasm of the VECs. This increases
eNOS activity via myoendothelial gap junctions, that transmit
vasodilatory NO signals to the underlying smooth muscle cells. VECs
appear to be sensitive to oxidative damage, which may be the result of
the conversion of NO to peroxynitrite (ONOO-) in the
presence of the harmful ROS; superoxide
(O2-) that ultimately reduces vascular
NO bioavailability (Endemann & Schiffrin, 2004; Kolluru, Bir & Kevil,
2012; Tabit, Chung, Hamburg & Vita, 2010). An altered oxidative balance
in VECs has been demonstrated to promote cardiovascular manifestations
such as atherosclerosis, myocardial infarction (MI) and stroke
(Brassington, Selemidis, Bozinovski & Vlahos, 2019; Endemann &
Schiffrin, 2004; Kolluru, Bir & Kevil, 2012; Tabit, Chung, Hamburg &
Vita, 2010).
Although cardiovascular comorbidities are the largest cause of mortality
in COPD, the detrimental effects of CS and its associated oxidative
stress on the systemic vasculature remain largely unknown. Given the
deleterious role of oxidative stress in COPD, antioxidant treatment may
be a viable therapeutic approach to treat the cardiovascular
manifestations associated with this disease. We have previously shown
that the antioxidant ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)one),
an organoselenium glutathione peroxidase (Gpx) mimetic, inhibits
CS-induced lung inflammation in mice (Duong, Seow, Bozinovski, Crack,
Anderson & Vlahos, 2010). Ebselen treatment may also be an effective
therapeutic in chronic diseases such as atherosclerosis, thrombosis, and
stroke where oxidative stress and inflammation play a crucial role (Azad
& Tomar, 2014; Sarker et al., 2003; Sarma & Mugesh, 2008; Takasago,
Peters, Graham, Masayasu & Macrae, 1997). Moreover, studies have shown
that Gpx-1 deficient mice have enhanced pulmonary inflammation (Duong,
Seow, Bozinovski, Crack, Anderson & Vlahos, 2010), as well as worsened
cardiovascular outcomes including a larger infarct volume following
ischemic stroke (Crack et al., 2001; Duong, Seow, Bozinovski, Crack,
Anderson & Vlahos, 2010), suggesting that Gpx-1 (or compounds which
mimic its actions, like ebselen) may exhibit protective effects.
Of interest, Gpx-1 activity has been shown to be elevated in smokers as
a potential mechanism to counteract the harmful oxidative stress.
However, Gpx-1 has been reported to be severely depleted in the lungs of
COPD patients, resulting in an overstated inflammatory response and
oxidative burden (Kluchova, Petrasova, Joppa, Dorkova & Tkacova, 2007;
Santos et al., 2004; Tkacova, Kluchova, Joppa, Petrasova & Molcanyiova,
2007; Vlahos et al., 2010). A study by Chew et.al has showcased
the therapeutic effect of ebselen in Gpx-1 knockout mice, with the study
finding that synthetic repletion of Gpx activity in these diabetic mice
produced athero-protective effects in vivo (Chew et al., 2010).
Exogenous repletion of Gpx-1 with compounds like ebselen may have
therapeutic potential in not only treating the pulmonary manifestations
of COPD but perhaps its cardiovascular comorbidities.
In the present study we
investigated whether chronic CS exposure in a preclinical mouse model of
COPD impairs vascular function and whether ebselen can prevent
CS-induced vascular dysfunction in mice.