Induction of human aortic myofibroblast-mediated extracellular matrix dysregulation: A potential mechanism of fluoroquinolone-associated aortopathy
| Autor: | Darrell D. Belke, Patrick Geeraert, Daniyil A. Svystonyuk, Sean Kang, David G. Guzzardi, Paul W.M. Fedak, Guoqi Teng, Simranjit S. Pattar |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
Pulmonary and Respiratory Medicine Necrosis Immunoblotting Aortic Diseases Fluorescent Antibody Technique Apoptosis 030204 cardiovascular system & hematology Matrix (biology) Matrix metalloproteinase Extracellular matrix 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Humans Propidium iodide Myofibroblasts Fluorescein isothiocyanate Aorta Cells Cultured business.industry Tissue Inhibitor of Metalloproteinases Middle Aged Molecular biology Extracellular Matrix 030228 respiratory system chemistry Female Surgery medicine.symptom Cardiology and Cardiovascular Medicine business Myofibroblast Extracellular Matrix Degradation Fluoroquinolones |
| Zdroj: | The Journal of Thoracic and Cardiovascular Surgery. 157:109-119.e2 |
| ISSN: | 0022-5223 |
| DOI: | 10.1016/j.jtcvs.2018.08.079 |
| Popis: | Objectives Fluoroquinolone (FQ) antibiotics are associated with adverse aortic clinical events. We assessed human aortic myofibroblast-mediated extracellular matrix (ECM) dysregulation as a possible cellular mechanism underlying FQ-associated aortopathy. Methods Human aortic myofibroblasts were isolated from patients with aortopathy undergoing elective ascending aortic resection (N = 9). The capacity for extracellular matrix degradation in cells exposed to FQ was assessed by multiplex analysis of secreted matrix metalloproteinases relative to tissue inhibitors of matrix metalloproteinases (TIMPs). Direct evaluation of extracellular matrix degradation was investigated in human aortic cells using a 3-dimensional gelatin-fluorescein isothiocyanate fluorescence microgel assay. Aortic cellular collagen-1 expression following FQ exposure was determined by immunoblotting and immunofluorescent staining. Cell apoptosis, necrosis, and metabolic viability was determined by annexin-V, propidium iodide staining, and water-soluble tetrazolium salt (WST1) assay. Results FQ exposure significantly decreased aortic cell TIMP-1 (P = .004) and TIMP-2 (P = .0004) protein expression compared with vehicle control. The ratio of matrix metalloproteinase-9/TIMP-2 was increased suggesting an increased capacity for extracellular matrix degradation (P = .01). In collagen gels, we show a trend toward increased aortic myofibroblast-mediated collagen fiber degradation with FQ exposure (P = .09). Similarly, FQ exposure attenuated collagen-1 expression as assessed by immunoblotting (P = .002) and immunofluorescence (P = .02). Cell apoptosis, necrosis, and metabolic viability was not significantly influenced by FQ exposure. Conclusions For the first time, we document a putative mechanism underlying FQ-associated aortopathy whereby decreased TIMP expression with impaired compensatory collagen-1 expression results in human aortic myofibroblast-mediated extracellular matrix dysregulation. These novel data may provide a cellular and molecular mechanism to explain the established clinical association between FQ exposure and acute aortic events. |
| Databáze: | OpenAIRE |
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