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Use of fluoroquinolone (FQ) antibiotics is common and widespread in the community. FQ are highly associated with connective tissue weakening causing severe tendon ruptures. Clinical studies have also shown increased aortic events after FQ exposure. It is possible that a similar mechanism of connective tissue weakening may exacerbate aortopathy leading to aortic rupture/dissection after exposure to FQ. Aortic fibroblasts mediate extracellular matrix (ECM) homeostasis and prevent aortic rupture by synthesizing collagen matrix and expressing endogenous protease inhibitors (TIMP). We hypothesized that FQ induces ECM dysregulation by downregulating collagen and TIMP expression thereby increasing the capacity for matrix metalloproteinase (MMP)-mediated ECM disruption.
Methods and Results
Human aortic fibroblasts were isolated from patients with aortopathy undergoing elective ascending aortic resection (N=4). Ciprofloxacin at a tissue-relevant concentration of 500uM was used as the representative FQ. We assessed the capacity for ECM degradation by comparing MMP and TIMP protein expression using multiplex in human aortic fibroblasts exposed to FQ for 48 hours versus 0.8uM hydrochloric acid vehicle control. FQ significantly decreased TIMP-1 (0.21 ± 0.08 vs 0.95 ± 0.24pg/mL, p=0.03) and TIMP-2 (0.27 ± 0.06 vs 1.12 ± 0.22pg/mL, p=0.01) concentrations. MMP-1, -3, -10 and -13 were unaffected by FQ. These data confirm an increased capacity for MMP-mediated ECM degradation. Aortic fibroblasts were stimulated with transforming growth factor -1 and incubated with FQ. Western blotting of cell lysate revealed decreased collagen-1 expression at 500uM FQ versus vehicle control (0.02 ± 0.01 vs 0.70 ± 0.08 optical density relative to GAPDH, p=0.01). Congruent with these findings, immunofluorescent staining of aortic fibroblasts showed decreased intracellular collagen-1 with FQ as compared to vehicle control (Figure 1B vs 1A). We assessed apoptosis and necrosis via annexin V and propidium iodide staining, respectively. Low and non-significantly different apoptosis/necrosis compared to vehicle control was observed (1.83 ± 1.09 vs 1.40 ± 0.40% apoptotic/necrotic cells, p=0.73). These data confirm that the observed effects were not the result of increased cell death from FQ exposure.
For the first time, we document that human aortic fibroblasts exposed to FQ show an increased capacity for ECM dysregulation by reduced collagen and TIMP protein expression. These data may provide a novel mechanism to explain the increased clinical incidence of aortic events for patients exposed to FQ. FQ may exacerbate aortopathy and these data suggest caution for use of FQ in such patients.