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. 1996 May 15;97(10):2384–2390. doi: 10.1172/JCI118682

Farnesyl analogues inhibit vasoconstriction in animal and human arteries.

J B Roullet 1, H Xue 1, J Chapman 1, P McDougal 1, C M Roullet 1, D A McCarron 1
PMCID: PMC507320  PMID: 8636420

Abstract

Recent studies have suggested that nonsterol, mevalonate-derived metabolites are implicated in the control of vascular tone and blood pressure. Because of the metabolic importance of farnesyl pyrophosphate, a 15-carbon (C15) intermediate of the cholesterol pathway, the vasoactive properties of the farnesyl motif were investigated. Two farnesyl analogues were used: farnesol, the natural dephosphorylated form of farnesyl pyrophosphate, and N-acetyl-S-trans,trans-farnesyl-L-cysteine (AFC), a synthetic mimic of the carboxyl terminus of farnesylated proteins. Both compounds inhibited NE-induced vasoconstriction in rat aortic rings at micromolar concentration. Their action was rapid, dose dependent, and reversible. Shorter (C10) and longer (C20) isoprenols as well as N-acetyl-S-geranyl-L-cysteine (C10) did not inhibit the response to NE. In contrast, N-acetyl-S-geranylgeranyl-L-cysteine (C20), exhibited vasoactive properties similar to AFC. It was further demonstrated that AFC and farnesol inhibited KCl and NaF-induced contractions, suggesting a complex action on Ca2+ channels and G protein-dependent pathways. Finally, the effect of farnesol and AFC on the NE response was reproduced in human resistance arteries. In conclusion, mevalonate-derived farnesyl analogues are potent inhibitors of vasoconstriction. The study suggests that farnesyl cellular availability is an important determinant of vascular tone in animals and humans, and provides a basis for exploring farnesyl metabolism in humans with compromised vascular function as well as for using farnesyl analogues as regulators of arterial tone in vivo.

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Selected References

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  1. Adeagbo A. S., Triggle C. R. Mechanism of vascular smooth muscle contraction by sodium fluoride in the isolated aorta of rat and rabbit. J Pharmacol Exp Ther. 1991 Jul 1;258(1):66–73. [PubMed] [Google Scholar]
  2. Benham C. D., Tsien R. W. Noradrenaline modulation of calcium channels in single smooth muscle cells from rabbit ear artery. J Physiol. 1988 Oct;404:767–784. doi: 10.1113/jphysiol.1988.sp017318. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bigay J., Deterre P., Pfister C., Chabre M. Fluoroaluminates activate transducin-GDP by mimicking the gamma-phosphate of GTP in its binding site. FEBS Lett. 1985 Oct 28;191(2):181–185. doi: 10.1016/0014-5793(85)80004-1. [DOI] [PubMed] [Google Scholar]
  4. Bradfute D. L., Simoni R. D. Non-sterol compounds that regulate cholesterogenesis. Analogues of farnesyl pyrophosphate reduce 3-hydroxy-3-methylglutaryl-coenzyme A reductase levels. J Biol Chem. 1994 Mar 4;269(9):6645–6650. [PubMed] [Google Scholar]
  5. Bønaa K. H., Thelle D. S. Association between blood pressure and serum lipids in a population. The Tromsø Study. Circulation. 1991 Apr;83(4):1305–1314. doi: 10.1161/01.cir.83.4.1305. [DOI] [PubMed] [Google Scholar]
  6. Casey P. J. Biochemistry of protein prenylation. J Lipid Res. 1992 Dec;33(12):1731–1740. [PubMed] [Google Scholar]
  7. Casey P. J. Protein lipidation in cell signaling. Science. 1995 Apr 14;268(5208):221–225. doi: 10.1126/science.7716512. [DOI] [PubMed] [Google Scholar]
  8. Chobanian A. Overview: hypertension and atherosclerosis. Am Heart J. 1988 Jul;116(1 Pt 2):319–322. doi: 10.1016/0002-8703(88)90108-1. [DOI] [PubMed] [Google Scholar]
  9. Chowienczyk P. J., Watts G. F., Cockcroft J. R., Ritter J. M. Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholesterolaemia. Lancet. 1992 Dec 12;340(8833):1430–1432. doi: 10.1016/0140-6736(92)92621-l. [DOI] [PubMed] [Google Scholar]
  10. Clarke S. Protein isoprenylation and methylation at carboxyl-terminal cysteine residues. Annu Rev Biochem. 1992;61:355–386. doi: 10.1146/annurev.bi.61.070192.002035. [DOI] [PubMed] [Google Scholar]
  11. Codina J., Birnbaumer L. Requirement for intramolecular domain interaction in activation of G protein alpha subunit by aluminum fluoride and GDP but not by GTP gamma S. J Biol Chem. 1994 Nov 25;269(47):29339–29342. [PubMed] [Google Scholar]
  12. Correll C. C., Ng L., Edwards P. A. Identification of farnesol as the non-sterol derivative of mevalonic acid required for the accelerated degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J Biol Chem. 1994 Jul 1;269(26):17390–17393. [PubMed] [Google Scholar]
  13. Corsini A., Mazzotti M., Raiteri M., Soma M. R., Gabbiani G., Fumagalli R., Paoletti R. Relationship between mevalonate pathway and arterial myocyte proliferation: in vitro studies with inhibitors of HMG-CoA reductase. Atherosclerosis. 1993 Jun;101(1):117–125. doi: 10.1016/0021-9150(93)90107-6. [DOI] [PubMed] [Google Scholar]
  14. Crick D. C., Waechter C. J., Andres D. A. Utilization of geranylgeraniol for protein isoprenylation in C6 glial cells. Biochem Biophys Res Commun. 1994 Nov 30;205(1):955–961. doi: 10.1006/bbrc.1994.2758. [DOI] [PubMed] [Google Scholar]
  15. Dolphin A. C. Regulation of calcium channel activity by GTP binding proteins and second messengers. Biochim Biophys Acta. 1991 Jan 10;1091(1):68–80. doi: 10.1016/0167-4889(91)90224-l. [DOI] [PubMed] [Google Scholar]
  16. Ericsson J., Appelkvist E. L., Thelin A., Chojnacki T., Dallner G. Isoprenoid biosynthesis in rat liver peroxisomes. Characterization of cis-prenyltransferase and squalene synthetase. J Biol Chem. 1992 Sep 15;267(26):18708–18714. [PubMed] [Google Scholar]
  17. Ericsson J., Runquist M., Thelin A., Andersson M., Chojnacki T., Dallner G. Distribution of prenyltransferases in rat tissues. Evidence for a cytosolic all-trans-geranylgeranyl diphosphate synthase. J Biol Chem. 1993 Jan 15;268(2):832–838. [PubMed] [Google Scholar]
  18. Falloon B. J., Bund S. J., Tulip J. R., Heagerty A. M. In vitro perfusion studies of resistance artery function in genetic hypertension. Hypertension. 1993 Oct;22(4):486–495. doi: 10.1161/01.hyp.22.4.486. [DOI] [PubMed] [Google Scholar]
  19. Gingras D., Boivin D., Béliveau R. Subcellular distribution and guanine nucleotide dependency of COOH-terminal methylation in kidney cortex. Am J Physiol. 1993 Aug;265(2 Pt 2):F316–F322. doi: 10.1152/ajprenal.1993.265.2.F316. [DOI] [PubMed] [Google Scholar]
  20. Hancock J. F., Magee A. I., Childs J. E., Marshall C. J. All ras proteins are polyisoprenylated but only some are palmitoylated. Cell. 1989 Jun 30;57(7):1167–1177. doi: 10.1016/0092-8674(89)90054-8. [DOI] [PubMed] [Google Scholar]
  21. Heistad D. D., Armstrong M. L., Marcus M. L., Piegors D. J., Mark A. L. Augmented responses to vasoconstrictor stimuli in hypercholesterolemic and atherosclerotic monkeys. Circ Res. 1984 Jun;54(6):711–718. doi: 10.1161/01.res.54.6.711. [DOI] [PubMed] [Google Scholar]
  22. Huzoor-Akbar, Wang W., Kornhauser R., Volker C., Stock J. B. Protein prenylcysteine analog inhibits agonist-receptor-mediated signal transduction in human platelets. Proc Natl Acad Sci U S A. 1993 Feb 1;90(3):868–872. doi: 10.1073/pnas.90.3.868. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kawase T., Van Breemen C. Aluminum fluoride induces a reversible Ca2+ sensitization in alpha-toxin-permeabilized vascular smooth muscle. Eur J Pharmacol. 1992 Apr 7;214(1):39–44. doi: 10.1016/0014-2999(92)90093-j. [DOI] [PubMed] [Google Scholar]
  24. MacMahon S. W., Macdonald G. J., Blacket R. B. Plasma lipoprotein levels in treated and untreated hypertensive men and women. The National Heart Foundation of Australia Risk Factor Prevalence Study. Arteriosclerosis. 1985 Jul-Aug;5(4):391–396. doi: 10.1161/01.atv.5.4.391. [DOI] [PubMed] [Google Scholar]
  25. Marshall C. J. Protein prenylation: a mediator of protein-protein interactions. Science. 1993 Mar 26;259(5103):1865–1866. doi: 10.1126/science.8456312. [DOI] [PubMed] [Google Scholar]
  26. Missiaen L., De Smedt H., Droogmans G., Himpens B., Casteels R. Calcium ion homeostasis in smooth muscle. Pharmacol Ther. 1992 Nov;56(2):191–231. doi: 10.1016/0163-7258(92)90017-t. [DOI] [PubMed] [Google Scholar]
  27. Mulvany M. J., Aalkjaer C. Structure and function of small arteries. Physiol Rev. 1990 Oct;70(4):921–961. doi: 10.1152/physrev.1990.70.4.921. [DOI] [PubMed] [Google Scholar]
  28. Munro E., Patel M., Chan P., Betteridge L., Clunn G., Gallagher K., Hughes A., Schachter M., Wolfe J., Sever P. Inhibition of human vascular smooth muscle cell proliferation by lovastatin: the role of isoprenoid intermediates of cholesterol synthesis. Eur J Clin Invest. 1994 Nov;24(11):766–772. doi: 10.1111/j.1365-2362.1994.tb01074.x. [DOI] [PubMed] [Google Scholar]
  29. Nebigil C., Malik K. U. Alpha adrenergic receptor subtypes involved in prostaglandin synthesis are coupled to Ca++ channels through a pertussis toxin-sensitive guanine nucleotide-binding protein. J Pharmacol Exp Ther. 1993 Aug;266(2):1113–1124. [PubMed] [Google Scholar]
  30. Nelson M. T., Standen N. B., Brayden J. E., Worley J. F., 3rd Noradrenaline contracts arteries by activating voltage-dependent calcium channels. Nature. 1988 Nov 24;336(6197):382–385. doi: 10.1038/336382a0. [DOI] [PubMed] [Google Scholar]
  31. O'Donnell M. P., Kasiske B. L., Kim Y., Atluru D., Keane W. F. Lovastatin inhibits proliferation of rat mesangial cells. J Clin Invest. 1993 Jan;91(1):83–87. doi: 10.1172/JCI116204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Philips M. R., Pillinger M. H., Staud R., Volker C., Rosenfeld M. G., Weissmann G., Stock J. B. Carboxyl methylation of Ras-related proteins during signal transduction in neutrophils. Science. 1993 Feb 12;259(5097):977–980. doi: 10.1126/science.8438158. [DOI] [PubMed] [Google Scholar]
  33. Pérez-Sala D., Tan E. W., Cañada F. J., Rando R. R. Methylation and demethylation reactions of guanine nucleotide-binding proteins of retinal rod outer segments. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3043–3046. doi: 10.1073/pnas.88.8.3043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Roullet J. B., Xue H., Pappu A. S., Roullet C., Holcomb S., McCarron D. A. Mevalonate availability and cardiovascular functions. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11728–11732. doi: 10.1073/pnas.90.24.11728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Roullet J. B., Xue H., Roullet C. M., Fletcher W. S., Cipolla M. J., Harker C. T., McCarron D. A. Mevalonate availability affects human and rat resistance vessel function. J Clin Invest. 1995 Jul;96(1):239–244. doi: 10.1172/JCI118027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Scheer A., Gierschik P. Farnesylcysteine analogues inhibit chemotactic peptide receptor-mediated G-protein activation in human HL-60 granulocyte membranes. FEBS Lett. 1993 Mar 15;319(1-2):110–114. doi: 10.1016/0014-5793(93)80047-x. [DOI] [PubMed] [Google Scholar]
  37. Sinensky M., Lutz R. J. The prenylation of proteins. Bioessays. 1992 Jan;14(1):25–31. doi: 10.1002/bies.950140106. [DOI] [PubMed] [Google Scholar]
  38. Somlyo A. P., Somlyo A. V. Signal transduction and regulation in smooth muscle. Nature. 1994 Nov 17;372(6503):231–236. doi: 10.1038/372231a0. [DOI] [PubMed] [Google Scholar]
  39. Tan E. W., Pérez-Sala D., Cañada F. J., Rando R. R. Identifying the recognition unit for G protein methylation. J Biol Chem. 1991 Jun 15;266(17):10719–10722. [PubMed] [Google Scholar]
  40. Volker C., Lane P., Kwee C., Johnson M., Stock J. A single activity carboxyl methylates both farnesyl and geranylgeranyl cysteine residues. FEBS Lett. 1991 Dec 16;295(1-3):189–194. doi: 10.1016/0014-5793(91)81415-5. [DOI] [PubMed] [Google Scholar]
  41. Volker C., Miller R. A., McCleary W. R., Rao A., Poenie M., Backer J. M., Stock J. B. Effects of farnesylcysteine analogs on protein carboxyl methylation and signal transduction. J Biol Chem. 1991 Nov 15;266(32):21515–21522. [PubMed] [Google Scholar]
  42. Wang Y., Townsend C., Rosenberg R. L. Regulation of cardiac L-type Ca channels in planar lipid bilayers by G proteins and protein phosphorylation. Am J Physiol. 1993 Jun;264(6 Pt 1):C1473–C1479. doi: 10.1152/ajpcell.1993.264.6.C1473. [DOI] [PubMed] [Google Scholar]
  43. Xue H., Bukoski R. D., McCarron D. A., Bennett W. M. Induction of contraction in isolated rat aorta by cyclosporine. Transplantation. 1987 May;43(5):715–718. doi: 10.1097/00007890-198705000-00022. [DOI] [PubMed] [Google Scholar]
  44. Zeng Y. Y., Benishin C. G., Pang P. K. Guanine nucleotide binding proteins may modulate gating of calcium channels in vascular smooth muscle. I. Studies with fluoride. J Pharmacol Exp Ther. 1989 Jul;250(1):343–351. [PubMed] [Google Scholar]
  45. Zeng Y. Y., Benishin C. G., Pang P. K. Guanine nucleotide binding proteins may modulate gating of calcium channels in vascular smooth muscle. II. Studies with guanosine 5'-(gamma)triphosphate. J Pharmacol Exp Ther. 1989 Jul;250(1):352–357. [PubMed] [Google Scholar]

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