Farnesyltransferase inhibitor R115777 protects against vascular disease in uremic mice

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• 作者：Igor G. Nikolov^a ; ^b ; ¹ ; ² ; Nobuhiko Joki^b ; ¹ ; Antoine Galmiche^a ; Thao Nguyen-Khoa^b ; ^c ; Ida Chiara Guerrera^d ; Franç ; ois Guillonneau^e ; Ognen Ivanovski^a ; Olivier Phan^a ; Julien Maizel^a ; Fré ; dé ; ric Març ; on^a ; Joyce Benchitrit^a ; ^b ; Anthony Lucas^c ; Aleksander Edelman^b ; ^d ; Bernard Lacour^c ; Tilman B. Dr&uuml ; eke^a ; Ziad A. Massy^a ; ^f ; ^{massy@u-picardie.fr} ; ^{ziad.massy@apr.aphp.fr}
• 关键词：Mevalonate pathway ; Farnesyltransferase inhibitor ; Chronic renal failure ; Calcification ; Atherosclerosis ; apoE&minus ; /&minus ; mouse
• 刊名：Atherosclerosis
• 出版年：2013
• 出版时间：July, 2013
• 年：2013
• 卷：229
• 期：1
• 页码：42-51
• 全文大小：2712 K

文摘

Background

Atherosclerosis and vascular calcification are major contributors to cardiovascular morbidity and mortality among chronic kidney disease patients. The mevalonate pathway may play a role in this vascular pathology. Farnesyltransferase inhibitors such as R115777 block one branch of mevalonate pathway. We studied the effects of farnesyltransferase inhibitor R115777 on vascular disease in apolipoprotein E deficient mice with chronic renal failure and on mineral deposition in?vitro.

Methods and results

Female uremic and non-uremic apolipoprotein E deficient mice were randomly assigned to four groups and treated with either farnesyltransferase inhibitor R115777 or vehicle. Farnesyltransferase inhibitor R115777 inhibited protein prenylation in mice with chronic renal failure. It decreased aortic atheromatous lesion area and calcification in these animals, and reduced vascular nitrotyrosine expression and total collagen as well as collagen type I content. Proteomic analysis revealed that farnesyltransferase inhibitor corrected the chronic renal failure-associated increase in serum apolipoprotein IV and ¦Á globin, and the chronic renal failure-associated decrease in serum fetuin A.?Farnesyltransferase inhibitor further inhibited type I collagen synthesis and reduced mineral deposition in vascular smooth muscle cells in?vitro, probably involving Ras-Raf pathway.

Conclusions

We show for the first time that farnesyltransferase inhibition slows vascular disease progression in chronic renal failure by both indirect systemic and direct local actions. This beneficial effect was mediated via a reduction in oxidative stress and favorable changes in vasoprotective peptides.