Michiko Sugita1, Hiroki Sugita, Masao Kaneki. 1. Department of Anesthesia & Critical Care, Massachusetts General Hospital, Harvard Medical School, 149 Thirteenth Street, Rm. 6604, Charlestown, MA 02129, USA.
Abstract
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. METHODS AND 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.
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. METHODS AND 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.
Authors: Behzad Yeganeh; Emilia Wiechec; Sudharsana R Ande; Pawan Sharma; Adel Rezaei Moghadam; Martin Post; Darren H Freed; Mohammad Hashemi; Shahla Shojaei; Amir A Zeki; Saeid Ghavami Journal: Pharmacol Ther Date: 2014-02-26 Impact factor: 12.310
Authors: Rebecca R Miles; William Perry; Joseph V Haas; Marian K Mosior; Mathias N'Cho; Jian W J Wang; Peng Yu; John Calley; Yong Yue; Quincy Carter; Bomie Han; Patricia Foxworthy; Mark C Kowala; Timothy P Ryan; Patricia J Solenberg; Laura F Michael Journal: J Biol Chem Date: 2013-01-15 Impact factor: 5.157
Authors: Brian C Capell; Michelle Olive; Michael R Erdos; Kan Cao; Dina A Faddah; Urraca L Tavarez; Karen N Conneely; Xuan Qu; Hong San; Santhi K Ganesh; Xiaoyan Chen; Hedwig Avallone; Frank D Kolodgie; Renu Virmani; Elizabeth G Nabel; Francis S Collins Journal: Proc Natl Acad Sci U S A Date: 2008-10-06 Impact factor: 11.205