Abstract
Background and Purpose: It is well established that both smokers and
patients with COPD are at a significantly heightened risk of
cardiovascular disease (CVD), although the mechanisms underpinning the
onset and progression of comorbid CVD are largely unknown. Here, we
explored whether cigarette smoke (CS) exposure impairs vascular function
in mice and given the well-known pathological role for oxidative stress
in COPD, whether the antioxidant compound ebselen prevents CS-induced
vascular dysfunction in mice. Experimental Approach: Male BALB/c mice
were exposed to either room air (sham) or CS generated from 9 cigarettes
per day, 5 days a week for 8 weeks. Mice were treated with ebselen
(10mg/kg, oral gavage once daily) or vehicle (5% w/v CM cellulose in
water) 1 h prior to the first CS exposure of the day. Upon sacrifice,
bronchoalveolar lavage fluid (BALF) was collected to assess pulmonary
inflammation and the thoracic aorta was excised to investigate vascular
endothelial and smooth muscle dilator responses ex-vivo. Key Results: CS
exposure caused a significant increase in lung inflammation which was
reduced by ebselen. CS also caused significant endothelial dysfunction
in the thoracic aorta which was attributed to a downregulation of eNOS
expression and increased vascular oxidative stress. Ebselen abolished
the aortic endothelial dysfunction seen in CS-exposed mice by reducing
the oxidative burden and preserving eNOS expression. Conclusion and
Implications: Targeting CS-induced oxidative stress with ebselen may
provide a novel means for treating the life-threatening pulmonary and
cardiovascular manifestations associated with cigarette smoking and
COPD.