Ciprofloxacin speeds up aging of blood vessel muscle cells caused by Angiotensin II by changing energy and stress pathways in aortic aneurysm and dissection
Ciprofloxacin may accelerate Angiotensin-II-induced vascular smooth muscle cell , contributing to aortic aneurysm and dissection.
Significant changes in cellular senescence-related signaling pathways were observed in aortic tissue from patients with aortic aneurysm and dissection compared to healthy donors.
Vascular smooth muscle cells (VSMCs) from patients exhibited a senescent phenotype, evidenced by elevated levels of p21, p16, and increased SA-β-gal activity.
Pretreatment with Ciprofloxacin promoted Angiotensin-II-induced cellular senescence in control VSMCs, indicated by decreased cell proliferation and increased senescence markers.
Ciprofloxacin and Angiotensin-II together increased cellular (ROS) levels beyond that of either treatment alone.
Ciprofloxacin impaired mitochondrial dynamics by suppressing , leading to mitochondrial dysfunction and increased ROS generation.
Treatment with an AMPK activator partially mitigated the negative effects of Ciprofloxacin on VSMC senescence.
Simplified
Aortic aneurysm and dissection (AAD) is a cardiovascular disease that poses a severe threat to life and has high morbidity and mortality rates. Clinical and animal-based studies have irrefutably shown that fluoroquinolones, a commonly prescribed antibiotic for treating infections, significantly increase the risk of AAD. Despite this, the precise mechanism by which fluoroquinolones cause AAD remains unclear. Therefore, this study aims to investigate the molecular mechanism and role of Ciprofloxacin definitively-a type of fluoroquinolone antibiotic-in the progression of AAD. Aortic transcriptome data were collected from GEO datasets to detect the genes and pathways expressed differently between healthy donors and AAD patients. Human primary Vascular Smooth Muscle Cells (VSMCs) were isolated from the aorta. After 72 h of exposure to 110ug/ml Ciprofloxacin or 100 nmol/L AngII, either or combined, the senescent cells were identified through SA-β-gal staining. MitoTracker staining was used to examine the morphology of mitochondria in each group. Cellular (ROS) levels were measured using MitoSox and DCFH-DA staining. Western blot assay was performed to detect the protein expression level. We conducted an analysis of transcriptome data from both healthy donors and patients with AAD and found that there were significant changes in cellular -related signaling pathways in the latter group. We then isolated and identified human primary VSMCs from healthy donors (control-VSMCs) and patients' (AAD-VSMCs) aortic tissue, respectively. We found that VSMCs from patients exhibited senescent phenotype as compared to control-VSMCs. The higher levels of p21 and p16 and elevated SA-β-gal activity demonstrated this. We also found that pretreatment with Ciprofloxacin promoted angiotensin-II-induced cellular senescence in control-VSMCs. This was evidenced by increased SA-β-gal activity, decreased cell proliferation, and elevation of p21 and p16 protein levels. Additionally, we found that Angiotensin-II (AngII) induced VSMC senescence by promoting ROS generation. We used DCFH-DA and mitoSOX staining to identify that Ciprofloxacin and AngII pretreatment further elevated ROS levels than the vehicle or alone group. Furthermore, JC-1 staining showed that mitochondrial membrane potential significantly declined in the Ciprofloxacin and AngII combination group compared to others. Compared to the other three groups, pretreatment of Ciprofloxacin plus AngII could further induce mitochondrial fission, demonstrated by mitoTracker staining and western blotting assay. Mechanistically, we found that Ciprofloxacin impaired the balance of mitochondrial fission and fusion dynamics in VSMCs by suppressing the phosphorylation of . This caused mitochondrial dysfunction and ROS generation, thereby elevating AngII-induced cellular senescence. However, treatment with the AMPK activator partially alleviated those effects. Our data indicate that Ciprofloxacin may accelerate AngII-induced VSMC senescence through modulating AMPK/ROS signaling and, subsequently, hasten the progression of AAD.
Key numbers
110 μg/ml
Increase in SA-β-gal positive cells
Ciprofloxacin concentration that promotes cellular .
p21 and p16
markers elevation
Markers used to assess VSMC .
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