title: Cardioprotection by farnesol: role of the mevalonate pathway.
abstract: OBJECTIVE
  Farnesol is a key metabolite of the mevalonate pathway and known as an antioxidant. We examined whether farnesol treatment protects the ischemic heart.
  
  
  METHODS
  Male Wistar rats were treated orally with 0.2, 1, 5, and 50 mg/kg/day farnesol/vehicle for 12 days, respectively. On day 13, the effect of farnesol treatment on cardiac ischemic tolerance and biochemical changes was tested. Therefore, hearts were isolated and subjected either to 30 min coronary occlusion followed by 120 min reperfusion to measure infarct size or to 10 min aerobic perfusion to measure cardiac mevalonate pathway end-products (protein prenylation, cholesterol, coenzyme Q9, coenzyme Q10, dolichol), and 3-nitrotyrosine (oxidative/nitrosative stress marker), respectively. The cytoprotective effect of farnesol was also tested in cardiomyocytes subjected to simulated ischemia/reperfusion.
  
  
  RESULTS
  Farnesol pretreatment decreased infarct size in a U-shaped dose-response manner where 1 mg/kg/day dose reached a statistically significant reduction (22.3±3.9% vs. 40.9±6.1% of the area at risk, p<0.05). Farnesol showed a similar cytoprotection in cardiomyocytes. The cardioprotective dose of farnesol (1 mg/kg/day) significantly increased the marker of protein geranylgeranylation, but did not influence protein farnesylation, cardiac tissue cholesterol, coenzyme Q9, coenzyme Q10, and dolichol. While the cardioprotective dose of farnesol did not influence 3-nitrotyrosine, the highest dose of farnesol (50 mg/kg/day) tested did not show cardioprotection, however, it significantly decreased cardiac 3-nitrotyrosine.
  
  
  CONCLUSIONS
  This is the first demonstration that oral farnesol treatment reduces infarct size. The cardioprotective effect of farnesol likely involves increased protein geranylgeranylation and seems to be independent of the antioxidant effect of farnesol.
authors.affiliation: Cardiovascular Research Group, Department of Biochemistry, University of Szeged, 6720, 9 Dóm tér, Szeged, Hungary.
authors.forename: Gergő
authors.initials: G
authors.lastname: Szűcs
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Murlasits
authors.forename: Szilvia
authors.initials: S
authors.lastname: Török
authors.forename: Gabriella F
authors.initials: GF
authors.lastname: Kocsis
authors.forename: János
authors.initials: J
authors.lastname: Pálóczi
authors.forename: Anikó
authors.initials: A
authors.lastname: Görbe
authors.forename: Tamás
authors.initials: T
authors.lastname: Csont
authors.forename: Csaba
authors.initials: C
authors.lastname: Csonka
authors.forename: Péter
authors.initials: P
authors.lastname: Ferdinandy
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D004286:Dolichols / Q000378:metabolism; D005204:Farnesol / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects; D017368:Protein Prenylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014451:Ubiquinone / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D004286:Dolichols; D014451:Ubiquinone; C002744:3-nitrotyrosine; D014443:Tyrosine; D005204:Farnesol; D002784:Cholesterol; D008798:Mevalonic Acid