Ciprofloxacin exacerbates dysfunction of smooth muscle cells in a microphysiological model of thoracic aortic aneurysm

• DOI: 10.1172/jci.insight.161729
• Publication Date: 2022-12-06T17:02:06Z
• Authors: Bitao Xiang; Mieradilijiang Ab...; Gang Liu; Xiaonan Zhou; Dingqian Liu; Shichao Zhu; Yang Ming; Xiujie Yin; Shiqiang Yan; Yongxin Sun; Hao Lai; Chunsheng Wang; Jun Li; Kai Zhu
• Keywords: 0301 basic medicine; 0303 health sciences; Aortic Aneurysm, Thoracic; Myocytes, Smooth Muscle; R; Heart Valve Diseases; Vascular biology; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Bicuspid Aortic Valve Disease; Ciprofloxacin; Aortic Valve; Medicine; Animals; Humans; Research Article

Ciprofloxacin use may be associated with adverse aortic events. However, the mechanism underlying the effect of ciprofloxacin on the progression of thoracic aortic aneurysm (TAA) is not well understood. Using an in vitro microphysiological model, we treated human aortic smooth muscle cells (HASMCs) derived from patients with bicuspid aortic valve- or tricuspid aortic valve-associated (BAV- or TAV-associated) TAAs with ciprofloxacin. TAA C57BL/6 mouse models were utilized to verify the effects of ciprofloxacin exposure. In the microphysiological model, real-time PCR, Western blotting, and RNA sequencing showed that ciprofloxacin exposure was associated with a downregulated contractile phenotype, an upregulated inflammatory reaction, and extracellular matrix (ECM) degradation in the normal HASMCs derived from the nondiseased aorta. Ciprofloxacin induced mitochondrial dysfunction in the HASMCs and further increased apoptosis by activating the ERK1/2 and P38 mitogen-activated protein kinase pathways. These adverse effects appeared to be more severe in the HASMCs derived from BAV- and TAV-associated TAAs than in the normal HASMCs when the ciprofloxacin concentration exceeded 100 μg/mL. In the aortic walls of the TAA-induced mice, ECM degradation and apoptosis were aggravated after ciprofloxacin exposure. Therefore, ciprofloxacin should be used with caution in patients with BAV- or TAV-associated TAAs.