FGF21 Attenuates Er Stress Injury In Cardiomyocytes Via FGFR1-ERK1/2 Signaling Pathway

Objective: To explore the cardioprotective effect and mechanism of fibroblast growth factor 21(FGF21) in endoplasmic reticulum stress (ERS)-induced cardiomyocyte injury.Methods: The expression of FGF21 and its related receptors in rat cardiomyocytes (H9c2),heart and liver were measured by semi-quantitative PCR, western blot and immunofluorescence.Cardiomyocyte ERS model was established in H9c2 cells by 24 h induction with various concentrations of tunicamycin (TM),in which cell survival rate was studied by CCK-8 assay. The effect of ERS on the expression of PERK and JNK pro-apoptosis pathway,FGF21 and its main receptor was measured by western blot. FGF21 were overexpressed from pcDNA4 vector and its effect on cell viability and expression of key proteins in ER-stress signaling pathways were studied by cell viability assay, flow cytometry, Western and TUNEL assays. H9c2 cells were pretreated with FGFR1 inhibitor PD166866 (100 nM) or ERK1/2 inhibitor PD98059 (20 ?M) for 1 h, detected the influence of FGF21 cardioprotection effect in H9c2 cells under ER stress.Results: 1. FGF21 and the main receptors FGFR1 and ?-Klotho were indeed expressed in H9c2 cells and heart tissue. 2. Various degrees of ERS induced cardiomyocyte injury and up-regulated the activation of ERS-realted apoptosis pathways, and this increase reached plateau at 10 ?M final concentration of TM. 3. At the early stage of ERS(TM ? 10 ?M), the proteins levels of FGF21,p-FGFR1 and ?-Klotho increased and peaked at 10 ?M final concentration of TM, then decreased gradually with the aggravation of ERS. 4. FGF21 overexpression significantly inhibited ERS-realted apoptosis pathways, which in turn reduced the EBS-incuded cell apoptosis. 5. FGF21 overexpression also activated ERK1/2, p-FGFR1 and ?-Klotho. 6. Afther treatment with FGF21 and ERK1/2 inhibitors, the inhibition of EBS-induced apoptosis by FGF21 overexpression was significantly abolished, which in turn promoted the expression of pro-apoptotic proteins and induced cell death.Conclusions: As an endogenous protective factor in cardiovascular diseases, FGF21 effectively ameliorated ERS-induced apoptosis in cardiomyocytes by promoting cell survival through activating the FGFR1-ERK1/2 pathways.