FXR In Pressure Overload-Induced Cardiac Remodeling:Its Role And Underlying Mechanisms

Objective: Farnesoid X receptor(FXR),a transcriptional factor belongs to the nuclear receptor superfamily,is expressed in various tissues,including the liver,intestine and the heart etc.FXR has been shown to play an important role in bile acid,glucose and lipid metabolism.However,the biological function of FXR in the heart remains largely unexplored.This study aimed to examine the role of FXR in pathological cardiac remodeling.Methods and Results: Using genetic approaches with systemic FXR knock-out(KO)mice(C57BL/6J background),we established a central role for the FXR in the regulation of pressure overload-induced cardiac remodeling,and determined the mechanism underlying this process.Cardiac remodeling was induced by transverse aortic constriction(TAC),and was evaluated by echocardiographic,haemodynamic,pathological,and molecular analyses.Our results demonstrated that the loss of FXR ameliorated pressure overload-induced cardiac hypertrophy,fibrosis,and dysfunction.These beneficial effects were associated with the anti-apoptosis,anti-oxidative stress,intensifying the autophagy flux,and reversing the downregulation of whole metabolic gene during cardiac remoding.Analysis of signaling pathways revealed upregulated cAMP-response element binding protein(CREB)phosphorylation in response to FXR deletion.EMSA experiments confirmed that FXR ablation enhanced CREB DNA binding activity after TAC surgery.Furthermore,the inactivation of CREB by r AAV9 mediated cardiac specific CREB gene interference reverse the protective effect of FXR KO in pressure overload-induced cardiac remodeling.Conclusion: The findings of the present study show a key role for FXR in regulating the cardiac remodeling induced by pressure overload likely through its regulatory effects on the oxidative stress,apoptosis,autophagy and metabolic gene expression.These results provide new insight into the pathogenesis of myocardial remodeling.However,additional studies are needed to test whether modification of FXR function might improve the clinical outcome in cases of human cardiac hypertrophy or other cardiac diseases.