Ciprofloxacin Increases Susceptibility To Aortic Dissection And Rupture In Mice
Circulation(2017)
摘要
Rationale and Objective: Fluoroquinolones are among the most commonly prescribed antibiotics. Two observational clinical studies have indicated that fluoroquinolone use may be associated with an increased risk of aortic aneurysm and dissection (AAD). In this study, we tested the hypothesis that ciprofloxacin, the most commonly used fluoroquinolone, increases the risk of AAD in a mouse model of sporadic AAD. Approach and Results: Four-week-old male and female C57BL/6J mice were unchallenged or challenged with a high-fat diet (HFD) and low-dose angiotensin infusion (AngII, 1000 ng/min/kg). During the four-week period of AngII infusion, challenged mice also received either ciprofloxacin (100 mg/kg/day) (n=39) or vehicle (n=28) through daily gavage. While 75% of challenged mice developed aortic enlargement in thoracic and/or abdominal segments, only 18% developed aortic dissection and none had rupture. In contrast, challenged mice that received ciprofloxacin had a significantly increased incidence of aortic dissection (49%, p=0.01) and rupture (18%, p=0.035). Aortic tissues from challenged mice treated with ciprofloxacin showed markedly increased aortic destruction, elastic fiber fragmentation, matrix metalloproteinase (MMP) activity, and activation of the necroptosis pathway compared to controls. Experiments performed in male and female mice yielded similar results. To explore the direct effects of ciprofloxacin on the aortic wall, we treated aortic smooth muscle cells with ciprofloxacin and found that it reduced fibrilin-1, elastin, and TIMP-1 levels, and increased the level of MMP-9, suggesting that ciprofloxacin may reduce the biosynthesis of extracellular matrix (ECM) while promoting MMP activation and ECM destruction. Additionally, ciprofloxacin induced caspase-3 cleavage and apoptotic cell death. Conclusions: Our findings demonstrate that ciprofloxacin increases susceptibility to aortic dissection and rupture by promoting ECM destruction in a mouse model of sporadic AAD, supporting concerns raised in observational clinical studies and suggesting that this drug should be used with caution in patients with aortic dilatation.
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关键词
Aortic diseases, Surgery
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