title: Inhibition of farnesyl pyrophosphate synthase improves pressure overload induced chronic cardiac remodeling.
abstract: Farnesyl pyrophosphate synthase (FPPS) is a key enzyme in the mevalonate pathway. In our previous studies, we find that inhibition of FPPS attenuates angiotensin II-induced cardiac hypertrophy and fibrosis by suppressing RhoA while FPPS and Ras are up-regulated in pressure overload rats. In this study, we evaluate the effects and mechanisms of FPPS inhibition in pressure overload mice. Male FPPS-small interfering RNA (SiRNA) transgenic (Tg) mice and non-transgenic littermate control (NLC) were randomly divided into suprarenal abdominal aortic constriction (AAC) group and sham operation group. 12 weeks following AAC, mice were sacrificed by cervical dislocation. Histological and echocardiographic assessments showed that inhibition of FPPS improved chronic cardiac remodeling which was induced by AAC. The reductions of Ras farnesylation and GTP-Ras, as well as their downstream extracellular signal-related kinases 1/2 (ERK1/2) expression were observed in the heart of Tg-AAC mice compared with NLC-AAC mice, along with the reduction of fetal gene expression. We provide here important experimental evidence that inhibition of FPPS improves AAC induced chronic cardiac remodeling and fibrosis by the reduction of farnesylated Ras and the downregulation of Ras-ERK1/2 pathway.
authors.affiliation: From the Institute of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, PR China.
authors.forename: Chen-Ze
authors.initials: CZ
authors.lastname: Zhao
authors.affiliation: From the Institute of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, PR China.
authors.forename: Xu-Ming
authors.initials: XM
authors.lastname: Zhao
authors.affiliation: From the Institute of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Ultrasound, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, PR China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Mou
authors.affiliation: Department of Cardiology, Hangzhou First Municipal Hospital and Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
authors.affiliation: From the Institute of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, PR China.
authors.forename: Huan-Dong
authors.initials: HD
authors.lastname: Wu
authors.affiliation: From the Institute of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, PR China.
authors.forename: Dong-Pu
authors.initials: DP
authors.lastname: Dai
authors.affiliation: From the Institute of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ding
authors.affiliation: From the Institute of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, PR China.
authors.forename: Shen-Jiang
authors.initials: SJ
authors.lastname: Hu
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000601:surgery; D001794:Blood Pressure; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000473:pathology; D015536:Down-Regulation; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D020257:Ventricular Remodeling / Q000502:physiology*; D018631:ras Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D051228:Geranyltranstransferase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D020559:Monomeric GTP-Binding Proteins; D018631:ras Proteins; D020742:rhoA GTP-Binding Protein; D008798:Mevalonic Acid; D002118:Calcium