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Ebselen reduces cigarette smoke‐induced endothelial dysfunction in mice
Author(s) -
Brassington Kurt,
Chan Stanley M. H.,
Seow Huei Jiunn,
Dobric Aleksandar,
Bozinovski Steven,
Selemidis Stavros,
Vlahos Ross
Publication year - 2021
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15400
Subject(s) - ebselen , oxidative stress , enos , medicine , endothelial dysfunction , dilator , inflammation , bronchoalveolar lavage , thoracic aorta , copd , lung , pharmacology , endocrinology , aorta , nitric oxide , glutathione peroxidase , superoxide dismutase , nitric oxide synthase
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 co‐morbid 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 nine cigarettes per day, 5 days a week for 8 weeks. Mice were treated with ebselen (10 mg·kg −1 , 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 killing, 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 down‐regulation 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.