title: Effect of farnesyltransferase inhibition on cardiac remodeling in spontaneously hypertensive rats.
abstract: BACKGROUND
  Farnesyltransferase (FT), an essential enzyme at the downstream of mevalonate pathway, was reported to be upregulated in hypertrophic cardiomyocytes of spontaneously hypertensive rats (SHRs) compared with myocardium of Wistar-Kyoto rats (WKYs). This upregulation was accompanied with cardiac remodeling. This study was designed to determine whether FT inhibition can alter cardiac remodeling in SHRs.
  
  
  METHODS
  Twelve-week-old SHRs were randomized to receive infusion of either NS or FTI-276 (307 μg/kg/d i.v. each n=10). WKY rats served as normal controls (n=6). Echocardiography was performed before and after intervention. SHR hearts were perfused ex vivo for the evaluation of cardiac performance, collagen deposition and biochemical changes (activation of Ras, extracellular-signal regulated kinases/ERK1/2, procollagen type І/Ш, TGF-β1, connective tissue growth factor/CTGF, and bone morphogenetic protein-7/BMP-7 expression).
  
  
  RESULTS
  FTI-276 intervention decreased interventricular septum wall thickness at end- diastole (IVSd) and relative wall thickness (RWT) of SHRs (P<0.05). Three week intervention with FTI-276 attenuated hydroxyproline content (P<0.05), collagen deposition (P<0.01), Ras activation, ERK1/2 phosphorylation (P<0.01) and mRNA expression of procollagen type I, TGF-β1 and CTGF and elevated mRNA expression of BMP-7 (P<0.05) in left ventricle of SHRs.
  
  
  CONCLUSIONS
  The present study indicated that FT inhibition could attenuate myocardial fibrosis and partly improve cardiac remodeling in SHRs. The beneficial effects might be mediated through suppression of the activation of Ras and ERK1/2 phosphorylation pathway. The enhanced mRNA expression of BMP-7 with inhibition of TGF-β1 and CTGF mRNA expression might be an important mechanism.
authors.affiliation: Department of Neurology, The First Affiliated Hospital, College of Medicine, Zhejiang University, PR China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Han
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.forename: Kai-Jun
authors.initials: KJ
authors.lastname: Wang
authors.forename: Shen-Jiang
authors.initials: SJ
authors.lastname: Hu
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D009924:Organ Culture Techniques; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
chemical_list: C404062:FTI 276; D008715:Methionine; D051231:Farnesyltranstransferase
keywords: 3-hydroxy-3-methyl-glutaryl coenzyme A; ACh; B-type natriuretic peptide; BMP; BNP; CTGF; CVF; Cardiac remodeling; EF; ERK1/2; FPP; FT; FTI; FTI-276; Farnesyltransferase inhibitor; GADPH; HDL-C; HMG-CoA; HMI; HR; Hyp; Hypertension; I/R; IVS; LDL-C; LVEDP; LVID; LVM; LVMI; LVPW; LVSP; MAP; MVA; Myocardial fibrosis; NS; PE; RBD; RT-PCR; RWT; Ras binding domain; SBP; SHR; SNP; Smad; TC; TG; TGF-β1; WHM; WKY; Wistar-Kyoto rat; acetylcholine; bone morphogenetic protein; collagen volume fraction; connective tissue growth factor; ejection fraction; extracellular-signal regulated kinases 1/2; farnesyl pyrophosphate; farnesyltransferase; farnesyltransferase inhibitor; glyceraldehyde-3-phosphate dehydrogenase; heart mass index; heart rate; high-density lipoprotein cholesterol; hydroxyproline; interventricular septum; ischemia/reperfusion; left ventricular end-diastolic pressure; left ventricular internal diameter; left ventricular mass index; left ventricular posterior wall thickness; left ventricular systolic pressure; low-density lipoprotein cholesterol; mean arterial pressure; mevalonate; normal saline; phenylephrine; real-time polymerase chain reaction; relative wall thickness; small mother against decapentaplegic; sodium nitroprusside; spontaneously hypertensive rat; systolic blood pressure; the mass of left ventricle; the mass of the whole heart; total cholesterol; transforming growth factor-beta 1; triglyceride