Farnesyltransferase inhibitor, manumycin a, prevents atherosclerosis development and reduces oxidative stress in apolipoprotein E-deficient mice.
OBJECTIVE
Statins are presumed to exert their antiatherogenic effects in part via lipid-lowering-independent mechanisms. Inhibition of protein farnesylation and/or geranylgeranylation by statins has been postulated to contribute to the lipid-lowering-independent effects. However, a role for protein farnesylation in atherogenesis has not yet been studied. Therefore, we examined the effects of farnesyltransferase inhibitor, manumycin A, on the development of atherosclerosis in apolipoprotein E (apoE)-deficient mice fed a high-fat diet.


RESULTS
Manumycin A treatment for 22 weeks decreased Ras activity, and reduced fatty streak lesion size at the aortic sinus to 43% of that in vehicle-treated apoE-deficient mice (P<0.05), while plasma total cholesterol was unaltered. Moreover, manumycin A reduced alpha-smooth muscle actin-positive area to 29% of that in vehicle-treated apoE-deficient mice (P<0.01). The prevention of atherogenesis by manumycin A was accompanied by amelioration of oxidative stress, as judged by reduced ex vivo superoxide production and nitrotyrosine immunoreactivity.


CONCLUSIONS
These results indicate that the inhibition of farnesyltransferase prevents the development of mature atherosclerosis with concomitant alleviation of oxidative stress in apoE-deficient mice. The present data highlight farnesyltransferase as a potential molecular target for preventive and/or therapeutic intervention against atherosclerosis.
Sugita
Michiko
M
Department of Anesthesia & Critical Care, Massachusetts General Hospital, Harvard Medical School, 149 Thirteenth Street, Rm. 6604, Charlestown, MA 02129, USA.
Sugita
Hiroki
H
Kaneki
Masao
M
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004041:Dietary Fats; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D011090:Polyenes / Q000494:pharmacology* / Q000627:therapeutic use; D053284:Polyunsaturated Alkamides / Q000494:pharmacology* / Q000627:therapeutic use; D017368:Protein Prenylation; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D012850:Sinus of Valsalva / Q000187:drug effects / Q000473:pathology; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D001057:Apolipoproteins E; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D013481:Superoxides; C002744:3-nitrotyrosine; D014443:Tyrosine; D051231:Farnesyltranstransferase; D019908:Proto-Oncogene Proteins c-raf; D018631:ras Proteins; C054474:manumycin