The Role And Mechanism Of Farnesyl Pyrophosphate Synthase In Mouse Myocardial Remodeling

Background: One of the leading causes of morbidity and mortality worldwide is heart failure caused by cardiac remodeling,including cardiac hypertrophy and fibrosis,which can be induced by different factors.The mevalonate pathway(MVA)is the pathway for the synthesis of cholesterol in mammalian cells,and in addition to being involved in cholesterol synthesis,it is also involved in isoprenylation of proteins.Studies have shown that the key enzymes of the mevalonate pathway are abnormally expressed in myocardial remodeling in spontaneously hypertensive rats and pressure overload rats,suggesting that MVA key enzymes may play an important role in the process of myocardial remodeling.Farnesyl pyrophosphate synthase(FPPS)is located at the branch point of MVA and plays an extremely important role in transporting small GTP-binding proteins,which is essential for the function of myocardial cells.Therefore,FPPS expression disorders can lead to pathological cardiac hypertrophy.Objective: This study uses the FPPS cardiac specific knockout model to determine the role of FPPS in myocardial remodeling and the underlying molecular mechanisms.Method:(1)Construct a cardiac-specific knockout FPPS mouse model.(2)Real-time PCR,Western Blot and other methods were used to detect the myocardial specific knockout efficiency.(3)After determination,use echocardiography to analyze heart function in mice at different ages.(4)Mice were euthanized,heart tissue was taken,and heart weight ratio was measured.(5)Histopathological analysis of mouse heart function,degree of fibrosis,and morphological changes.(6)Real-time PCR was used to determine the expressions of cardiac cardiac hypertrophy genes(ANP,BNP,β-MHC)and cardiac fibrosis genes(TGF,CTGF,Procol-I,ProcolIII)in mice.(7)The GPP,FPP and GGPP levels in cardiomyocytes were detected using HPLC technology.(8)Measuring cholesterol in myocardial tissue.(9)The activity of small G proteins such as Ras and RHEB in mouse hearts was measured using the pull-down method.(10)Western Blot method was used to detect changes in protein levels downstream of the mouse heart FPPS protein pathway.Result:(1)The expression of FPPS in myocardial tissue of knockout mice was significantly reduced.(2)Echocardiography suggests that cardiomyocyte-specific FPPS knockout mice will suffer from cardiac decompensation.Histopathological analysis revealed an enlarged cardiac cavity and myocardial tissue fibrosis.(3)The expression of cardiac hypertrophy genes(ANP,BNP,β-MHC)and cardiac fibrosis genes(TGF,CTGF,Procol-I,Procol-III)were increased.(4)The content of FPP and GGPP decreased with the accumulation of GPP in vivo.(5)Ras,RHEB active forms are significantly increased,accompanied by downstream phosphorylation of ERK,m TOR expression is up-regulated.Conclusion: FPPS plays an important role in myocardial remodeling,and its mechanism may be related to the excessive activation of Ras and RHEB proteins,which will cause downstream ERK and m TOR expression to be upregulated and cause cardiac decompensation.