Effect of PD-1 inhibitor on aggravating radiation-induced myocardial injury by catalyzing pyroptosis
Objective To investigate the effects of programmed cell death protein-1(PD-1)inhibitor on radiation-induced myocardial injury through the pyroptosis pathway.Methods Twenty male C57BL/6 mice were randomized into four groups,namely the control group,the PD-1 inhibitor group,the cardiac radiation group(with a single dose of 20 Gy),and the combined group treated with both cardiac radiation and PD-1 inhibitor,with five mice in each group.At 1 month post-irradiation,echocardiography was performed to assess left ventricular ejection fraction(LVEF),stroke volume(SV),and left ventricular fractional shortening(LVFS);Hematoxylin-eosin(HE)and Masson staining were employed to observe the pathological changes in myocardial tissue;Western blot and real-time reverse transcription-quantitative polymerase chain reaction(RT-qPCR)were used to determine the expression of pyroptosis-related key factors in myocardial tissue such as cysteine aspartate specific proteinase-1(Caspase-1),gasdermin D(GSDMD),and apoptosis-associated speck-like protein containing CARD(ASC).Enzyme-linked immunosorbent assay(ELISA)was performed to determine the expression of interleukin-18(IL-18)and interleukin-1β(IL-1β).Furthermore,flow cytometry was used to evaluate the infiltration of myocardial lymphocytes.Results Compared to the radiation group,the mice in the combined group exhibited lower LVEF,FS and SV(t=4.50,27.93,3.11,P＜0.05),more significant myocardial injury and fibrosis,elevated myocardial collagen volume fraction[(2.88±0.27)％vs.(3.81±0.57)％,t=2.90,P＜0.05)],increased expression of Caspase-1,Caspase-1 p20,GSDMD,GSDMD-N,and ASC(t=3.14,3.22,8.83,20.29,2.79,P＜0.05),increased mRNA expression of Caspase-1,GSDMD and ASC(t=3.09,2.91,2.53,P＜0.05),increased expression of IL-18 and IL-1β in myocardium and serum(t=3.46,3.75,7.58,8.24,P＜0.05),and higher percentage of CD8+T lymphocytes[(38.33±7.92)％vs.(54.70±4.01)％,t=3.29,P＜0.05].However,there was no significant difference in the percentage of CD4+T lymphocytes among the groups(P＞0.05).Conclusions PD-1 inhibitor may catalyze pyroptosis via caspase-1/GSDMD,thus aggravating radiation-induced myocardial injury.
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