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Ebselen reduces cigarette smoke-induced vascular endothelial dysfunction in mice
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  • Kurt Brassington,
  • Stanley Chan,
  • Huei Seow,
  • Aleksandar Dobric,
  • Steven Bozinovski,
  • Stavros Selemidis,
  • Ross Vlahos
Kurt Brassington
RMIT University
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Stanley Chan
RMIT University
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Huei Seow
RMIT University
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Aleksandar Dobric
RMIT University
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Steven Bozinovski
RMIT University
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Stavros Selemidis
RMIT University
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Ross Vlahos
RMIT University
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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.

Peer review status:UNDER REVIEW

03 Sep 2020Submitted to British Journal of Pharmacology
03 Sep 2020Assigned to Editor
03 Sep 2020Submission Checks Completed
09 Sep 2020Reviewer(s) Assigned