核受体共激活因子4介导的铁自噬对阿霉素致心脏毒性的影响OA

Objective To investigate the effects of nuclear receptor coactivator 4(NCOA4)-mediated ferritinophagy on doxorubicin(DOX)-induced cardiotoxicity.Methods Twelve 8-week-old male C57BL/6J mice were randomly divided into groups A and B.Mice in group B were intraperitoneally injected with DOX,while those in group A received an equal volume of nor-mal saline.Rat cardiomyocyte H9c2 cells were divided into groups C to L.Groups C,E,and I were cultured under normal condi-tions;groups D,F,and J were treated with DOX;group G was treated with the ferroptosis inhibitor Fer-1 plus DOX;group H was treated with the iron chelator deferoxamine plus DOX;and groups K and L were transfected with si-NC and si-NCOA4,re-spectively,and then treated with DOX.Additional H9c2 cells were treated with DOX and cultured for 0,3,6,12,and 24 h.Wes-tern blot was used to detect the protein expression levels of NCOA4 and FTH1 in mouse heart tissues from the two groups and in each cell group.Cell viability was measured by CCK-8 assay.Serum lactate dehydrogenase(LDH)levels in the two groups of mice were measured using an LDH assay kit.Malondialdehyde(MDA)levels in mouse heart tissues and in each cell group were mea-sured using an MDA assay kit.Ferrous ion(Fe2+)levels in mouse serum and in each cell group were measured using a ferrous ion colorimetric assay kit.Results Animal experiments showed that compared with group A,group B exhibited significantly increased serum LDH and Fe2+levels,and cardiac tissue MDA level and NCOA4 protein expression level,and significantly decreased FTH1 protein expression level(t=3.69-16.15,P＜0.001).Cell experiments showed that compared with group C,group D exhibited sig-nificantly decreased cell viability,and significantly increased MDA and Fe2+levels(t=6.58-81.23,P＜0.001).Compared with 0 h,NCOA4 protein expression level in H9c2 cells was significantly increased and FTH1 protein expression level was significantly de-creased after 24 h of DOX treatment(F=11.04,6.46,q=5.92,5.53,P＜0.05).Compared with group E,group F showed signifi-cantly decreased cell viability and significantly increased MDA level.Compared with group F,groups G and H showed significantly increased cell viability and significantly decreased MDA levels(F=35.40,195.70,q=4.89-24.03,P＜0.01).Compared with group I,group J showed significantly decreased cell viability and significantly increased MDA and Fe2+levels.Compared with group J,group L showed significantly increased cell viability and significantly decreased MDA and Fe2+levels(F=67.45-565.90,q=9.63-303.60,P＜0.001).Conclusion DOX-induced cardiotoxicity is closely associated with NCOA4-mediated ferritinophagy in cardiomyocytes,and inhibition of NCOA4-mediated ferritinophagy alleviates DOX-induced cardiotoxicity.