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Cardiovascular Drugs and Therapy

, Volume 27, Issue 4, pp 269–277 | Cite as

Cardioprotection by Farnesol: Role of the Mevalonate Pathway

  • Gergő Szűcs
  • Zsolt Murlasits
  • Szilvia Török
  • Gabriella F. Kocsis
  • János Pálóczi
  • Anikó Görbe
  • Tamás Csont
  • Csaba Csonka
  • Péter Ferdinandy
ORIGINAL ARTICLE

Abstract

Purpose

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.

Keywords

Ischemia/reperfusion Protein geranylgeranylation Peroxynitrite Farnesol Mevalonate pathway 

Notes

Acknowledgments

This work was supported by a grant from the National Innovation Office (5LET_STATIN_08, TAMOP-4.2.2-08/1/2008-0013, TAMOP-4.2.1/B-09/1/KONV-2010-0005, TÁMOP-4.2.2/B-10/1-2010-0012, and TAMOP-4.2.2/A-11/1/KONV-2012-0035) and a grant from the Hungarian Scientific Research Fund (OTKA PD 106001). A. Görbe and T. Csont hold a “János Bolyai Fellowship” from the Hungarian Academy of Sciences.

References

  1. 1.
    Ferdinandy P, Schulz R, Baxter GF. Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning. Pharmacol Rev. 2007;59:418–58.PubMedCrossRefGoogle Scholar
  2. 2.
    Ferdinandy P, Csonka C, Csont T, Szilvassy Z, Dux L. Rapid pacing-induced preconditioning is recaptured by farnesol treatment in hearts of cholesterol-fed rats: role of polyprenyl derivatives and nitric oxide. Mol Cell Biochem. 1998;186:27–34.PubMedCrossRefGoogle Scholar
  3. 3.
    Qamar W, Sultana S. Farnesol ameliorates massive inflammation, oxidative stress and lung injury induced by intratracheal instillation of cigarette smoke extract in rats: an initial step in lung chemoprevention. Chem Biol Interact. 2008;176:79–87.PubMedCrossRefGoogle Scholar
  4. 4.
    Jahangir T, Khan TH, Prasad L, Sultana S. Farnesol prevents Fe-NTA-mediated renal oxidative stress and early tumour promotion markers in rats. Hum Exp Toxicol. 2006;25:235–42.PubMedCrossRefGoogle Scholar
  5. 5.
    Khan R, Sultana S. Farnesol attenuates 1,2-dimethylhydrazine induced oxidative stress, inflammation and apoptotic responses in the colon of Wistar rats. Chem Biol Interact. 2011;192:193–200.PubMedCrossRefGoogle Scholar
  6. 6.
    Crick DC, Andres DA, Waechter CJ. Farnesol is utilized for protein isoprenylation and the biosynthesis of cholesterol in mammalian cells. Biochem Biophys Res Commun. 1995;211:590–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature. 1990;343:425–30.PubMedCrossRefGoogle Scholar
  8. 8.
    Resh MD. Trafficking and signaling by fatty-acylated and prenylated proteins. Nat Chem Biol. 2006;2:584–90.PubMedCrossRefGoogle Scholar
  9. 9.
    Leung KF, Baron R, Seabra MC. Thematic review series: lipid posttranslational modifications. geranylgeranylation of Rab GTPases. J Lipid Res. 2006;47:467–75.PubMedCrossRefGoogle Scholar
  10. 10.
    Reddy S, Comai L. Lamin A, farnesylation and aging. Exp Cell Res. 2012;318:1–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol. 2001;21:1712–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Aberg F, Appelkvist EL, Dallner G, Ernster L. Distribution and redox state of ubiquinones in rat and human tissues. Arch Biochem Biophys. 1992;295:230–4.PubMedCrossRefGoogle Scholar
  13. 13.
    Greenberg S, Frishman WH. Co-enzyme Q10: a new drug for cardiovascular disease. J Clin Pharmacol. 1990;30:596–608.PubMedCrossRefGoogle Scholar
  14. 14.
    Hano O, Thompson-Gorman SL, Zweier JL, Lakatta EG. Coenzyme Q10 enhances cardiac functional and metabolic recovery and reduces Ca2+overload during postischemic reperfusion. Am J Physiol. 1994;266:2174–81.Google Scholar
  15. 15.
    Doucey MA, Hess D, Cacan R, Hofsteenge J. Protein C-mannosylation is enzyme-catalysed and uses dolichyl-phosphate-mannose as a precursor. Mol Biol Cell. 1998;9:291–300.PubMedCrossRefGoogle Scholar
  16. 16.
    Takeda J, Kinoshita T. GPI-anchor biosynthesis. Trends Biochem Sci. 1995;20:367–71.PubMedCrossRefGoogle Scholar
  17. 17.
    Kornfeld R, Kornfeld S. Assembly of asparagine-linked oligosaccharides. Annu Rev Biochem. 1985;54:631–64.PubMedCrossRefGoogle Scholar
  18. 18.
    Ferdinandy P, Schulz R. Nitric oxide, superoxide, and peroxynitrite in myocardial ischaemia-reperfusion injury and preconditioning. Br J Pharmacol. 2003;138:532–43.PubMedCrossRefGoogle Scholar
  19. 19.
    Yasmin W, Strynadka KD, Schulz R. Generation of peroxynitrite contributes to ischemia-reperfusion injury in isolated rat hearts. Cardiovasc Res. 1997;33:422–32.PubMedCrossRefGoogle Scholar
  20. 20.
    Kocsis GF, Pipis J, Fekete V, et al. Lovastatin interferes with the infarct size-limiting effect of ischemic preconditioning and postconditioning in rat hearts. Am J Physiol Heart Circ Physiol. 2008;294:2406–9.CrossRefGoogle Scholar
  21. 21.
    Csonka C, Kupai K, Kocsis GF, et al. Measurement of myocardial infarct size in preclinical studies. J Pharmacol Toxicol Methods. 2010;61:163–70.PubMedCrossRefGoogle Scholar
  22. 22.
    Epstein WW, Lever D, Leining LM, Bruenger E, Rilling HC. Quantitation of prenylcysteines by a selective cleavage reaction. Proc Natl Acad Sci U S A. 1991;88:9668–70.PubMedCrossRefGoogle Scholar
  23. 23.
    Rousseau G, Varin F. Determination of ubiquinone-9 and 10 levels in rat tissues and blood by high-performance liquid chromatography with ultraviolet detection. J Chromatogr Sci. 1998;36:247–52.PubMedCrossRefGoogle Scholar
  24. 24.
    Dini B, Dolfi C, Santucci V, et al. Effects of ageing and increased haemolysis on the levels of dolichol in rat spleen. Exp Gerontol. 2001;37:99–105.PubMedCrossRefGoogle Scholar
  25. 25.
    Csont T, Gorbe A, Bereczki E, et al. Biglycan protects cardiomyocytes against hypoxia/reoxygenation injury: role of nitric oxide. J Mol Cell Cardiol. 2010;48:649–52.PubMedCrossRefGoogle Scholar
  26. 26.
    Li X, Heinzel FR, Boengler K, Schulz R, Heusch G. Role of connexin 43 in ischemic preconditioning does not involve intercellular communication through gap junctions. J Mol Cell Cardiol. 2004;36:161–3.PubMedCrossRefGoogle Scholar
  27. 27.
    Bentinger M, Grunler J, Peterson E, Swiezewska E, Dallner G. Phosphorylation of farnesol in rat liver microsomes: properties of farnesol kinase and farnesyl phosphate kinase. Arch Biochem Biophys. 1998;353:191–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Ali BR, Nouvel I, Leung KF, Hume AN, Seabra MC. A novel statin-mediated “prenylation block-and-release” assay provides insight into the membrane targeting mechanisms of small GTPases. Biochem Biophys Res Commun. 2010;397:34–41.PubMedCrossRefGoogle Scholar
  29. 29.
    Lane KT, Beese LS. Thematic review series: lipid posttranslational modifications. Structural biology of protein farnesyltransferase and geranylgeranyltransferase type I. J Lipid Res. 2006;47:681–99.PubMedCrossRefGoogle Scholar
  30. 30.
    Brar BK, Jonassen AK, Egorina EM, et al. Urocortin-II and urocortin-III are cardioprotective against ischemia reperfusion injury: an essential endogenous cardioprotective role for corticotropin releasing factor receptor type 2 in the murine heart. Endocrinology. 2004;145:24–35.PubMedCrossRefGoogle Scholar
  31. 31.
    Xiang SY, Vanhoutte D, Del Re DP, et al. RhoA protects the mouse heart against ischemia/reperfusion injury. J Clin Invest. 2011;121:3269–76.PubMedCrossRefGoogle Scholar
  32. 32.
    Dougherty CJ, Kubasiak LA, Frazier DP, et al. Mitochondrial signals initiate the activation of c-Jun N-terminal kinase (JNK) by hypoxia-reoxygenation. FASEB J. 2004;18:1060–70.PubMedCrossRefGoogle Scholar
  33. 33.
    Matejikova J, Kucharska J, Pancza D, Ravingerova T. The effect of antioxidant treatment and NOS inhibition on the incidence of ischemia-induced arrhythmias in the diabetic rat heart. Physiol Res. 2008;57 Suppl 2:55–60.Google Scholar
  34. 34.
    Molyneux SL, Florkowski CM, Richards AM, Lever M, Young JM, George PM. Coenzyme Q10; an adjunctive therapy for congestive heart failure? N Z Med J. 2009;122:74–9.PubMedGoogle Scholar
  35. 35.
    Kapusta L, Zucker N, Frenckel G et al. From discrete dilated cardiomyopathy to successful cardiac transplantation in congenital disorders of glycosylation due to dolichol kinase deficiency (DK1-CDG). Heart Fail Rev. 2012;18:187-96Google Scholar
  36. 36.
    Lefeber DJ, de Brouwer AP, Morava E, et al. Autosomal recessive dilated cardiomyopathy due to DOLK mutations results from abnormal dystroglycan O-mannosylation. PLoS Genet. 2011;7:e1002427.PubMedCrossRefGoogle Scholar
  37. 37.
    Chagas CE, Vieira A, Ong TP, Moreno FS. Farnesol inhibits cell proliferation and induces apoptosis after partial hepatectomy in rats. Acta Cir Bras. 2009;24:377–82.PubMedCrossRefGoogle Scholar
  38. 38.
    Joo JH, Liao G, Collins JB, Grissom SF, Jetten AM. Farnesol-induced apoptosis in human lung carcinoma cells is coupled to the endoplasmic reticulum stress response. Cancer Res. 2007;67:7929–36.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Gergő Szűcs
    • 1
  • Zsolt Murlasits
    • 2
    • 3
  • Szilvia Török
    • 1
  • Gabriella F. Kocsis
    • 1
  • János Pálóczi
    • 1
  • Anikó Görbe
    • 1
  • Tamás Csont
    • 1
    • 3
  • Csaba Csonka
    • 1
    • 3
  • Péter Ferdinandy
    • 3
    • 4
  1. 1.Cardiovascular Research Group, Department of BiochemistryUniversity of SzegedSzegedHungary
  2. 2.Department of Health and Sport SciencesUniversity of MemphisMemphisUSA
  3. 3.Pharmahungary GroupSzegedHungary
  4. 4.Department of Pharmacology and PharmacotherapySemmelweis UniversityBudapestHungary

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