Induction of human aortic myofibroblast-mediated extracellular matrix dysregulation: A potential mechanism of fluoroquinolone-associated aortopathy David.

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Induction of human aortic myofibroblast-mediated extracellular matrix dysregulation: A potential mechanism of fluoroquinolone-associated aortopathy David G. Guzzardi, PhD, Guoqi Teng, PhD, Sean Kang, BSc, BKin, Patrick J. Geeraert, Simranjit S. Pattar, MBT, Daniyil A. Svystonyuk, PhD, Darrell D. Belke, PhD, Paul W.M. Fedak, MD, PhD The Journal of Thoracic and Cardiovascular Surgery Volume 157, Issue 1, Pages 109-119.e2 (January 2019) DOI: 10.1016/j.jtcvs.2018.08.079 Copyright © 2018 The American Association for Thoracic Surgery Terms and Conditions

Figure 1 Characterization of human aortic adventitial myofibroblasts. A, Cells stained positive for markers of myofibroblasts: vimentin (green), fibronectin (orange), and fibroblast surface protein (FSP) (orange). B, Cells stained negative for markers of nonmyofibroblast cells of the aortic wall: smoothelin (orange), desmin (green) (both indicative of smooth muscle cells), and von Willibrand factor (vWF; endothelial cells) (green). Immunofluorescent staining of indicated protein is in orange or green; nuclear staining (Hoechst stain) is in blue. White line indicates scale. The Journal of Thoracic and Cardiovascular Surgery 2019 157, 109-119.e2DOI: (10.1016/j.jtcvs.2018.08.079) Copyright © 2018 The American Association for Thoracic Surgery Terms and Conditions

Figure 2 Abundances of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) protein released by human aortic myofibroblasts exposed to fluoroquinolone (FQ), relative to untreated cells. A and B, TIMP-1 and -2. C and D, Ratios of MMP-9 to TIMP-1 and TIMP-2 concentrations. Horizontal lines denote median values and P values indicate comparison to 0 μM FQ (Friedman's test with Dunn's test for multiple comparisons). There were 5 replicates for panels A and C and 6 replicates for panels B and D. The Journal of Thoracic and Cardiovascular Surgery 2019 157, 109-119.e2DOI: (10.1016/j.jtcvs.2018.08.079) Copyright © 2018 The American Association for Thoracic Surgery Terms and Conditions

Figure 3 Assessment of human aortic myofibroblast-mediated gelatinase activity (compared to background) by 3-dimensional fluorescein isothiocyanate (FITC)-conjugated gelatin in response to fluoroquinolone exposure. A, Representative images of cell gelatin-FITC fluorescence. Top row, Human aortic myofibroblast (phalloidin stain, orange) and nuclear (Hoechst stain, blue) staining. Middle row, Cell gelatin-FITC fluorescence (green) relative to background fluorescence. Bottom row, Merged images. B, Quantification of cell gelatin-FITC fluorescence relative to untreated cells. Horizontal lines denote median values and P value indicates comparison to 0 μM fluoroquinolone (Friedman's test with Dunn's test for multiple comparisons). There were 4 replicates. White line indicates scale. FQ, Fluoroquinolone. The Journal of Thoracic and Cardiovascular Surgery 2019 157, 109-119.e2DOI: (10.1016/j.jtcvs.2018.08.079) Copyright © 2018 The American Association for Thoracic Surgery Terms and Conditions

Figure 4 Collagen-1 expression in human aortic myofibroblasts exposed to fluoroquinolone (FQ). A and B, Representative collagen-1 Western blot and quantified optical density relative to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) loading control; (6 replicates). C and D, Immunofluorescent staining of collagen-1 (green) and nuclei (Hoechst stain, blue). Horizontal lines denote median values and P values indicate comparison to 0 μM FQ (Friedman's test with Dunn's test for multiple comparisons). There were 4 replicates. White line indicates scale. The Journal of Thoracic and Cardiovascular Surgery 2019 157, 109-119.e2DOI: (10.1016/j.jtcvs.2018.08.079) Copyright © 2018 The American Association for Thoracic Surgery Terms and Conditions

Figure 5 Apoptosis, necrosis, and cell metabolic activity of human aortic myofibroblasts exposed to fluoroquinolone (FQ). A, Representative flow cytometry of cells double-stained with annexin-V (fluorescein isothiocyanate [FITC]) and propidium iodide (phycoerythrin [PE]). Percentages of late apoptotic/necrotic and early apoptotic cells are shown in the top right quadrants (Q2 and Q4, respectively). B, Percent of late apoptotic/necrotic cells are shown. C, Percent of early apoptotic cells are shown. D, Comparison of cell metabolic activity for different FQ exposures using water-soluble tetrazolium salt assay relative to untreated cells. Horizontal lines denote median values and P values denote comparison between 100, 250, and 500 μM FQ and 0 μM FQ (Friedman's test with Dunn's test for multiple comparisons). There were 4 replicates. The Journal of Thoracic and Cardiovascular Surgery 2019 157, 109-119.e2DOI: (10.1016/j.jtcvs.2018.08.079) Copyright © 2018 The American Association for Thoracic Surgery Terms and Conditions

Figure 6 Fluoroquinolone-induced human aortic myofibroblast-mediated extracellular matrix (ECM) dysregulation. Fluoroquinolone antibiotics generate an imbalance in metalloproteinases (MMPs) and tissue inhibitor of MMPs (TIMPs) resulting in ECM degradation alongside impaired myofibroblast-mediated collagen expression. These findings support a putative mechanism underlying fluoroquinolone drug exposure and the increased incidence of aortic aneurysm. The Journal of Thoracic and Cardiovascular Surgery 2019 157, 109-119.e2DOI: (10.1016/j.jtcvs.2018.08.079) Copyright © 2018 The American Association for Thoracic Surgery Terms and Conditions

Figure E1 Comparison of tissue inhibitor of matrix metalloproteinase (TIMP) protein released by human aortic (blue) and atrial (red) myofibroblasts exposed to fluoroquinolone (FQ), relative to untreated cells. A and B, TIMP-1 and -2. Horizontal lines denote median values. Within-aortic group comparisons to 0 μM FQ (Friedman's test with Dunn's test for multiple comparisons): *P = .004. ‡P = .04. #P = .0004. There were 5 and 6 replicates for aortic myofibroblasts in Panel A and Panel B, respectively. There were 2 replicates for atrial myofibroblasts. The Journal of Thoracic and Cardiovascular Surgery 2019 157, 109-119.e2DOI: (10.1016/j.jtcvs.2018.08.079) Copyright © 2018 The American Association for Thoracic Surgery Terms and Conditions

Figure E2 Comparison of immunofluorescent staining of collagen-1 (green) and nuclei (Hoechst stain, blue) in human aortic (blue) and atrial (red) myofibroblasts exposed to fluoroquinolone (FQ). A, Representative images of human atrial cardiac myofibroblasts. B, Quantification of immunofluorescent collagen-1 staining. Horizontal lines denote median values. Within-aortic group comparison to 0 μM FQ (Friedman's test with Dunn's test for multiple comparisons): *P = .02. There were 4 and 2 replicates for aortic and atrial myofibroblasts, respectively. White line indicates scale. The Journal of Thoracic and Cardiovascular Surgery 2019 157, 109-119.e2DOI: (10.1016/j.jtcvs.2018.08.079) Copyright © 2018 The American Association for Thoracic Surgery Terms and Conditions

Fluoroquinolone induces aortic myofibroblast-mediated extracellular matrix dysregulation. The Journal of Thoracic and Cardiovascular Surgery 2019 157, 109-119.e2DOI: (10.1016/j.jtcvs.2018.08.079) Copyright © 2018 The American Association for Thoracic Surgery Terms and Conditions

The Journal of Thoracic and Cardiovascular Surgery 2019 157, 109-119 The Journal of Thoracic and Cardiovascular Surgery 2019 157, 109-119.e2DOI: (10.1016/j.jtcvs.2018.08.079) Copyright © 2018 The American Association for Thoracic Surgery Terms and Conditions