PII-181 - FLUOROQUINOLONES ATTRIBUTE AORTIC DISEASES THROUGH ENDOTHELIAL DYSFUNCTION.

K. Miyata¹, Y. Izawa-Ishizawa², H. Nishi², S. Itokazu², T. Miyata², K. Tsujinaka², M. Kondo², T. Niimura², F. Aizawa², K. Yagi², K. Kawada², M. Goda², K. Ishizawa²; ¹Department of Clinical Pharmacology and Therapeutics, University of Tokushima Graduate School of Biomedical Sciences, ²Tokushima University.

Background: Aortic aneurysm and dissection (AAD) are common aortic diseases with high mortality. The risks of AAD are including old age, smoking, and male sex. Recently, AAD have been reported as adverse events associated with fluoroquinolones. Previous studies using aneurysm model mouse have shown that fluoroquinolones could induce AAD via suppression of collagen synthesis and increased oxidative stress in tunica media, but their effects on the vascular endothelium are unknown. The aim of current study is to evaluate the effect of fluoroquinolones on the vascular endothelium during the development of AAD.

Methods: First, we analyzed the association between fluoroquinolones and AAD in clinical situation using VigiBase, the World Health Organization’s global database. Next, we performed in vitro experiments to test the effects of levofloxacin (LVFX), a fluoroquinolone, on the endothelial dysfunction using cultured human umbilical vein endothelial cells (HUVECs). To evaluate the influence of LVFX to development of arterial diseases in mice, we generated aortic dissection model mice, called LAB mouse, which were induced by three drugs; nitric oxide synthase inhibitor, angiotensin II, and lysyl oxidase inhibitor. The effects of LVFX on the progression of vascular diseases in LAB mice were investigated histologically and molecularly.

Results: VigiBase analysis showed that the fluoroquinolones had the association of high reporting rate of AAD.
Real-time PCR showed that LVFX treatment increased ICAM-1, VCAM-1, and E-Selectin expressions in HUVECs, which indicated endothelial dysfunction and inflammation. In LAB mice, LVFX challenge did not significantly influence the incidence of aortic dissection but tended to increase ICAM-1 and VCAM-1 expressions in aorta from LAB mice without aortic dissection onset.

Conclusion: Our results suggested that the endothelial dysfunction might be one candidate mechanism of fluoroquinolone-associated AAD onset.