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

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 (BAV)-or tricuspid aortic valve (TAV)-associated TAAs with ciprofloxacin. TAA C57/BL6 mouse models were utilized to verify the effects of ciprofloxacin exposure. In the microphysiological model, real-time polymerase chain reaction, 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 non-diseased 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.

Investigation of the Pathogenic Mechanism of Ciprofloxacin in Aortic Aneurysm and Dissection by an Integrated Proteomics and Network Pharmacology Strategy

“…This study only focused on VSMCs, and the conclusion may not be extended to other cellular components. Second, consistent with previous studies that explored the effect of ciprofloxacin on cellular function in vitro [ 55 , 56 ], the concentrations of CIP used in our study were 100-300 μg/mL. However, the peak concentration of CIP in human plasma is approximately 1.26 μg/mL after administration of a single oral dose of 250 mg [ 57 ].…”

Fluoroquinolones increase susceptibility to aortic aneurysm and aortic dissection: Molecular mechanism and clinical evidence

“…52 The expression of TIMP1/2 of VSMCs in a human aortic microphysiological model was significantly down-regulated after ciprofloxacin (200 µg/mL) treatment. 48 Furthermore, ciprofloxacin exposure significantly reduced TIMPs and collagen secretion in aortic myoblasts, resulting in a significant increase in the MMP-9/TIMP-2 ratio. 53 Ciprofloxacin not only directly or indirectly induces the enhancement of MMPs, but also destroys the structural stability of the ECM fibrin.…”

“…Ciprofloxacin (200 µg/mL) decreased the mRNA levels of COL I/IV in cultured human arterial smooth muscle cells (SMCs). 48 Ciprofloxacin (100 mg/kg/day) increases the activity of MMPs and the level of MMP-9 49 in the aortic wall of mice with AA and AD. Ciprofloxacin (100 mg/kg/day) significantly promotes the deterioration of aortic elastic fiber structure in rats with Marfan syndrome and considerably elevates the expression of Mmp2 and Mmp9 .…”

“…49 Xiang et al found that ciprofloxacin (200 µg/mL) induced mitochondrial dysfunction in human aortic VSMCs and promoted apoptosis via the P38 and ERK1/2 MAPK pathways. 48 Previously, VSMCs were classified as contractile and synthetic/proliferative phenotypes. As the primary type of VSMCs, contractile VSMCs not only maintain the integrity of the aortic wall, but also provide them with abundant tension and active elasticity to avoid excessive expansion of the aorta in response to blood pressure.…”

“…The decreased expression of contractile phenotypic markers suggests the transformation of VSMCs to synthesis, and the secretion of OPN and MMP-2 leads to remodeling of the aortic wall structure. 48,51 Al-Neklawy et al conducted pathological staining of sections from rats treated with ciprofloxacin, revealing multiple tissue losses in the tunica media, disordered arrangement of VSMCs, abnormal reduction in the number of VSMCs, and most notably, an increase in eosinophilic VSMCs, which may be the result of VSMCs injury. The diminished immunohistochemical staining of α-smooth muscle actin (αSMA) in the ciprofloxacin-treated group was indicative of phenotypic transition of VSMCs.…”