3-nitrotyrosine and Vascular-Calcification

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.. 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 α 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.. 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.

Topics: Animals; Aorta; Apolipoproteins E; Apoptosis; Atherosclerosis; Blood Proteins; Body Weight; Collagen Type I; Enzyme Inhibitors; Farnesyltranstransferase; Female; Kidney Failure, Chronic; Liver; Macrophages; Mevalonic Acid; Mice; Mice, Knockout; Muscle, Smooth, Vascular; Prenylation; Quinolones; Random Allocation; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tyrosine; Uremia; Vascular Calcification

Cardiovascular disease in chronic kidney disease (CKD) has peculiar characteristics. The aim of this study was to analyze atherosclerosis, vascular calcification and nitration in arteries from CKD patients.. External iliac and renal artery segments from 27 stage 5 CKD patients and 25 donor controls, respectively, were collected during the transplantation procedure.. CKD patients presented a significantly higher degree of lesion. In a large proportion (72%) of CKD patients, we observed vascular calcifications. Immunohistochemistry for nitrotyrosine revealed a significant increase in nitrotyrosine production in arteries from CKD patients compared with control donors. In addition, within CKD patients, nitrotyrosine staining was significantly stronger in arteries with media calcification when compared with arteries without media calcification.. The arteriopathy in the CKD patients appears in an early age and seems to be distinct from the arteriopathy of the general population, especially due to intense calcification and vascular oxidative stress.

Topics: Adult; Atherosclerosis; Case-Control Studies; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Proteins; Renal Artery; Risk Factors; Tyrosine; Vascular Calcification