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Ciprofloxacin exacerbates dysfunction of smooth muscle cells in a microphysiological model of thoracic aortic aneurysm
Bitao Xiang, … , Jun Li, Kai Zhu
Bitao Xiang, … , Jun Li, Kai Zhu
Published December 6, 2022
Citation Information: JCI Insight. 2023;8(2):e161729. https://doi.org/10.1172/jci.insight.161729.
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Research Article Vascular biology

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

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Abstract

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.

Authors

Bitao Xiang, Mieradilijiang Abudupataer, Gang Liu, Xiaonan Zhou, Dingqian Liu, Shichao Zhu, Yang Ming, Xiujie Yin, Shiqiang Yan, Yongxin Sun, Hao Lai, Chunsheng Wang, Jun Li, Kai Zhu

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Figure 7

Increased apoptosis in the aortic wall of the BAPN-induced TAA mice after ciprofloxacin treatment.

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Increased apoptosis in the aortic wall of the BAPN-induced TAA mice afte...
(A) Representative images of TUNEL staining in the thoracic aortic wall among the groups (n = 3, scale bars: 50 μm) and (B) quantification of TUNEL-negative cells (TUNEL-positive cells marked in green). (C) Representative images of Western blotting of total CASP3, Bcl2, Bax, and cleaved CASP3 and quantification of the total band densities for (D) Bax, (E) Bax/Bcl2, (F) Bcl2, and (G) cleaved CASP3/total CASP3 normalized to the corresponding band density of α-tubulin (n = 6). (H) Representative images of Western blotting of p-P38, P38, p-ERK1/2, and ERK1/2 and quantification of the total band densities for (I) p-P38/P38 and (J) p-ERK1/2/ERK1/2 normalized to the corresponding band density of α-tubulin (n = 6). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by 1-way ANOVA with Tukey’s multiple-comparison test. (K) Potential mechanism of ciprofloxacin-induced apoptosis and negative effects in the HASMCs of the TAA-induced mice. Ciprofloxacin could induce the degradation of COL I and COL IV, reduction in SM22 and CNN1, and upregulation of IL-1β, IL-6, MMP2, and MMP9. Meanwhile, it could induce HASMC mitochondrial dysfunction and further increase apoptosis through upregulation of Bax, Bax/Bcl2, and cleaved CASP3, presumably followed by aortic wall damage.

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