The Effection Of Farnesylpyrophosphate Synthas Inhibitor In Myocardial Remodeling

Part Ⅰ:FPPS inhibitor improves myocardial hypertrophy and remodeling of junk proteinsBackgroung:Hypertrophic cardiomyopathy is a group of clinical syndromes,of which the congestive heart failure is caused by excessive activation of the body’s neuroendocrine system and environmental imbalances.This constant and exaggerated hypertrophy would eventually lead to decreased cardiac output and chronic heart failure.During the entire process of the formation for heart failure,cardiac remodeling is a dynamic development and join throught out the alternatives,including apoptosis,myocardial fibrosis,adipose accumulation,mitochondrial anomalies,ion channel changes and changes in signal transduction pathways.Previous studies have shown that,FPPS(famesyl pyrophosphate synthase)is a key enzyme in the way of hydroxy-Pentanoic acid.The pyrophosphate catalyzed synthesis of products like FPP(Farnesyl pyrophosphate)and GGPP(Geranylgeranyl pyrophosphat)are directly involved in signal transduction pathways of cadiac hypertrophy and occurrence of cardiac remodeling.Fibrosis of the myocardial cells in cardiac remodeling is an important feature.Changes such as troponin,gap junction protein indirectly reflect the degree of myocardial remodeling and the way of communication between these cells can be an improved delivery and reversal for myocardial remodeling.Objective:to study the effection and function of famesyl pyrophosphate synthetase inhibitor in myocardial hypertrophy and remodeling in abdominal aortic coarctation animal models.Methods:1.Abdominal aorta constriction for cardiac hypertrophy in rats model is established;2.Male SD rats were randomly divided into 2 groups:the abdominal aorta coarctation group and Sham-operated group.Make sure for successful surgery,further SD rats were then divided into 3 groups:Sham-operated control group,surgery group and surgical intervention group.Given normal saline 10mg/kg/day and alendronate 10mg/kg/day lasting for 3,5 and 8 weeks.3.The application of echocardiography and hemodynamics detection both in model and FPPS inhibitors interfere rats to measure the histological changes;4.Measure left tibial length of both in model and FPPS inhibitors interfere rats;5.Use high performance liquid chromatography(HPLC)technique to evaluate FPP and GGPP levels;6.Use Rat BNP testing box to evaluate BNP levels in blood samples;7.Myocardial tissue sections stained with collagen type Ⅰ fibers(Col-I),troponin t(t-TnT)and Gap junctional protein(cx43)for immunohistochemical analysis.Results:1.Abdominal aorta constriction leads to cardiac hypertrophy in rats and increases FPP and GGPP levels in myocardial tissue;2.FPPS inhibitors can partially improve myocardial hypertrophy,and reduces the myocardial tissue contents of FPP and GGPP;3.Early period of cardiac hypertrophy and myocardial remodeling makes no significant changes in exercise tolerance and serum BNP level;4.Myocardial remodelingincluds myocardial fibrosis,and changes such as troponin and connexin.FPPS inhibitors can reverse refactoring on this cellular level.Conclusion:FPPS are involved in the occurrence and development of myocardial hypertrophy and remodeling;FPPS inhibitors can improve myocardial cell contact.Part Ⅱ:Research on the RhoA pathway in myocardial hypertrophy with farnesyl pyrophosphate synthetase inhibitorBackgroud:Cardiac remodeling is an important event in development of pathological processes for hypertrophic cardiomyopathy and eventually leads to heart failure.Many studies show that RhoA/ROCK pathway that are activated by the protein-mediated takes part in myocardial hypertrophy and apoptosis occurrence.Rho kinase belonging to the small G-proteins(protein kinase A,QC)family of serine/threonine kinases,through Rock effect of target molecules and raw materials such as cell proliferation,adhesion,migration,and many biological behavior and functionality.RhoA/Rock signaling pathway make effect in left ventricular remodeling in the process of raised Inflammatory Cytokines,suppress contractile,promoting cardiac hypertrophy and cardiomyocyte apoptosis and myocardial fibrosis etc.FPPS inhibitor like allensodium phosphate is a classic drug,which can inhibit the FPP and GGPP formation and thus influence RhoA/Rock signaling transduction for myocardium hypertrophy and fibrosis in the pathological process.Famesyl pyrophosphate Synthase(FPPS)seems to be the treatment of myocardial hypertrophy and new targets to improve cardiac remodeling.Objective:To explore the possible mechanism of RhoA pathway on cardiac hypertrophy and remodeling with FPPS inhibitor.Methods:1.Abdominal aorta constriction for cardiac hypertrophy in rats model is established;2.Male SD rats were randomly divided into 3 groups:Sham-operated control group,surgery group and surgical intervention group.Given normal saline 10mg/kg/day and alendronate 10mg/kg/day lasting for 3,5 and 8 weeks.3.The application of echocardiography and hemodynamics detection both in model and FPPS inhibitors interfere rats to measure the histological changes;5.Use high performance liquid chromatography(HPLC)technique to evaluate FPP and GGPP levels;6.Use RhoA testing box to get OD level(490nm)both in model and FPPS inhibitors interfere rats;7.Measure the level of FDPS、RhoA and p-ERK1/2 by using western blot.Results:1.FPPS inhibitors can improve myocardial hypertrophy;2.FPPS inhibitors reduce the myocardial tissue contents of FPP and GGPP;3.FPPS inhibitors reduce the contents of RhoA;4.FPPS inhibitors improve the myocardial hypertrophy and remodeling by blotting the pathway of RhoA.Conclusion:With the inhibition in the expression of RhoA pathway,an improvement in left ventricular hypertrophy and cardiac remodeling can be observed by FPPS inhibitors usage;FPPS may be a new ideato treat myocardial hypertrophy.