TRIM38通过TRAF6-p38MAPK通路调节铁死亡参与心力衰竭的机制研究OA

Objective:To explore underlying mechanism by which TRIM38 participates in heart failure(HF)by regulating fer-roptosis through TRAF6-p38MAPK pathway.Methods:TRIM38 level in AC16 cells was knocked down by infecting with AdshTRIM38 adenovirus.Immunofluorescence was used to detect morphological changes of myocardial cells and GPX4 protein expression.Western blot and qRT-PCR were employed to detect protein and mRNA expressions of atrial natriuretic peptide(ANP)and brain natriuretic peptide(BNP).Western blot,ubiquitination and co-immunoprecipitation(Co-IP)were used to detect interaction between TRIM38 and TRAF6-p38MAPK pathway.A transverse aortic constriction(TAC)mouse HF model was established and divided into wild-type(WT)group and TRIM38 gene knockout(TRIM38-KO)group.After surgery,heart weight measurement,histopathological examina-tion,as well as Western blot and RT-qPCR detections were carried out.Results:Silencing TRIM38 increased size of AC16 cells and expressions of ANP,BNP and GPX4.TRIM38 interacted with TRAF6 and regulated its ubiquitination and p38MAPK phosphorylation.In vivo experiments showed that compared with WT mice,at 4 weeks after TAC surgery,heart weight,heart weight/body weight and heart weight/tibia length of TRIM38-KO mice were significantly increased.Histopathological results indicated that compared with TAC-WT group,TAC-TRIM38-KO group exhibited pathological hypertrophy of myocardial cells and aggravated myocardial fibrosis.Western blot and qRT-PCR showed that ANP,BNP,MYH7,Collagen Ⅰ a,Collagen Ⅲ,CTGF expressions,phosphorylation level of p38MAPK,and TRAF6 expression in heart tissue of TAC-TRIM38-KO mice were significantly increased.Immunofluorescence staining of TRIM38-KO mice revealed an increase in myocardial ferroptosis and cell apoptosis,and activation of TRAF6-p38MAPK pathway.Conclusion:TRIM38 participates in occurrence and development of HF by regulating ferroptosis through TRAF6-p38MAPK pathway.