Abstract 65P
Background
Radiation injury of blood vessels (RIBV) is a serious long-term complication of radiotherapy, and the main pathophysiological change of which is atherosclerosis. Senescence of vascular smooth muscle cells (VSMCs) is implicated in the pathogenesis of radiation-induced atherosclerosis. The mechanisms underlying VSMCs senescence, however, remain poorly understood.
Methods
Using cultured human aortic smooth cells (HASMC) and SD male explored whether IR could induce transformation of senescent phenotype of VSMCs. ChIP assay explored whether SICC bind to p16 gene in irradiated cells. SA-β-gal staining indicate radiation-induced senescence.
Results
Using cultured human aortic smooth cells (HASMC) and SD male rats showed that IR could induce transformation of senescent phenotype of VSMCs with significant positive dose and time dependence in vitro and in vivo. IR activated DDR/NF-κB pathway and induced the nuclear loss of HMGB2 and thus spatial aggregation of CTCF, known as senescence-induced CTCF clusters (SICC), but had no significant effect on the expression level of CTCF. And ChIP assay showed that SICC exhibited stronger binding ability to p16 gene in irradiated cells. Overexpressing HMGB2 and silencing CTCF abrogated radiation-stimulated p16 upregulation with less SICC formation. Suppression of the activation of NF-κB by PDTC (a common inhibitor of NF-κB) attenuated radiation-induced senescence, indicated by less SA-β-gal staining, downregulation of p16. We also found that PDTC reduced radiation-induced nuclear loss of HMGB2 and formation of SICC.
Conclusions
In summary, we demonstrated here, for the first time, that IR induced transformation of senescent phenotype of VSMCs in vivo and in vitro, and activated NF-κB pathway to initiate HMGB2 nuclear loss and thus promote the formation of SICC, which further strengthen the binding ability of CTCF and p16 gene, and resulted in the occurrence of radiation-induced senescence in VSMCs. These findings may have a significant impact on the research of radiation-induced atherosclerosis and open a new prospective in the prevention and therapeutic intervention in RIBV.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
National Natural Science Foundation of China.
Disclosure
All authors have declared no conflicts of interest.
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