3-nitrotyrosine and Uremia

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

Metabolic diseases such as hyperlipidemia and diabetes attenuate the cardioprotective effect of ischemic preconditioning. In the present study, we examined whether another metabolic disease, prolonged uremia, affects ischemia/reperfusion injury and cardioprotection by ischemic preconditioning. Uremia was induced by partial nephrectomy in male Wistar rats. The development of uremia was verified 29 wk after surgery. Transthoracic echocardiography was performed to monitor cardiac function. At week 30, hearts of nephrectomized and sham-operated rats were isolated and subjected to a 30-min coronary occlusion followed by 120 min reperfusion with or without preceding preconditioning induced by three intermittent cycles of brief ischemia and reperfusion. In nephrectomized rats, plasma uric acid, carbamide, and creatinine as well as urine protein levels were increased as compared with sham-operated controls. Systolic anterior and septal wall thicknesses were increased in nephrectomized rats, suggesting the development of a minimal cardiac hypertrophy. Ejection fraction was decreased and isovolumic relaxation time was shortened in nephrectomized rats demonstrating a mild systolic and diastolic dysfunction. Infarct size was not affected significantly by nephrectomy itself. Ischemic preconditioning significantly decreased infarct size from 24.8 ± 5.2% to 6.6 ± 1.3% in the sham-operated group and also in the uremic group from 35.4 ± 9.5% to 11.9 ± 3.1% of the area at risk. Plasma ANG II and nitrotyrosine were significantly increased in the uremic rats. We conclude that although prolonged experimental uremia leads to severe metabolic changes and the development of a mild myocardial dysfunction, the cardioprotective effect of ischemic preconditioning is still preserved.

Topics: Angiotensin II; Animals; Biomarkers; Creatinine; Disease Models, Animal; Ischemic Preconditioning, Myocardial; Male; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Nephrectomy; Proteinuria; Rats; Rats, Wistar; Stroke Volume; Time Factors; Tyrosine; Ultrasonography; Urea; Uremia; Uric Acid; Ventricular Function, Left

Chronic kidney disease (CKD) results in accelerated atherosclerosis and cardiovascular disease. This is primarily mediated by oxidative stress, inflammation and dyslipidemia. By mediating reverse cholesterol transport and exerting antioxidant/anti-inflammatory actions, high-density lipoprotein (HDL) and ApoA-1 protect against atherosclerosis. Plasma Apo-1, HDL cholesterol and HDL antioxidant/anti-inflammatory activities are reduced in CKD. ApoA-1 mimetic peptides associate with and enhance antioxidant/anti-inflammatory properties of HDL. We hypothesized that long-term administration of ApoA-1 mimetic peptide, L4F, may ameliorate inflammation and oxidative stress in the conduit arteries in experimental CKD.. After 5/6 nephrectomy, rats were randomized to L4F (5 mg/kg s.c. 3 times weekly for 4 weeks) and placebo-treated groups. Sham-operated rats served as controls.. The untreated CKD group exhibited marked lipid accumulation and upregulations of NAD(P)H oxidase subunits (gp91(phox), p22(phox), and p47(phox)), COX-2, 12-lipoxygenase, MCP-1, PAI-1, myeloperoxidase and iNOS, NFκB activation and nitrotyrosine accumulation in the thoracic aorta. L4F administration reversed or attenuated these abnormalities without altering renal function or plasma lipids.. CKD leads to lipid accumulation and upregulation of pro-atherogenic pathways in the artery wall. These abnormalities are attenuated by ApoA-1 mimetic peptide, pointing to its protective effect in CKD. Future studies are needed to explore the effect of these peptides in CKD patients.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Aorta, Thoracic; Apolipoprotein A-I; Arachidonate 12-Lipoxygenase; Arteritis; Atherosclerosis; Chemokine CCL2; Cyclooxygenase 2; Male; NADPH Oxidases; NF-kappaB-Inducing Kinase; Nitric Oxide Synthase Type II; Oxidative Stress; Peptides; Peroxidase; Plasminogen Activator Inhibitor 1; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Tyrosine; Up-Regulation; Uremia

Cardiovascular disease is the most frequent cause of mortality in chronic renal failure (CRF). Therefore, it is important to identify appropriate treatment measures. The antioxidant N-acetylcysteine (NAC) has been shown to reduce cardiovascular events in hemodialysis patients. Here we examine a possible direct effect of NAC supplementation on uremia-enhanced atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice.. Uremia was induced surgically in 8-week-old female apoE(-/-) mice. Two weeks after creation of CRF mice were randomized to receive either NAC (daily oral gavage with 200 mg/kg for 8 weeks) or placebo. They were compared to a control group of sham-operated apoE(-/-) mice receiving placebo. After 8 weeks of treatment, the mice were sacrificed, and the cross-section surface area of atherosclerotic plaques was measured in aortic root and descending aorta.. At 10 weeks following surgery, atherosclerotic lesions were significantly larger in uremic apoE(-/-) mice than in nonuremic controls. This accelerated atherosclerosis was associated with an increase in aortic nitrotyrosine expression and collagen plaque content. NAC treatment inhibited the progression of atherosclerotic lesions and plaque collagen content compared with placebo treatment. In addition, plaques from NAC-treated uremic animals showed a significant decrease in nitrotyrosine expression whereas the degree of macrophage infiltration was comparable in both uremic groups. There was no difference in mean arterial blood pressure between the three groups.. We show for the first time that the antioxidant NAC is capable of reducing atheroma progression, in an animal model of uremia-enhanced atherosclerosis, probably via a decrease in oxidative stress.

Topics: Acetylcysteine; Animals; Antioxidants; Aorta; Apolipoproteins E; Arteriosclerosis; Body Weight; Collagen; Female; Mice; Mice, Knockout; Tyrosine; Uremia

The novel phosphate binder sevelamer has been shown to prevent the progression of aortic and coronary calcification in uremic patients. Whether it also decreases the progression of atheromatous plaques is unknown. The aim of our study was to examine the effect of sevelamer administration on the development of atherosclerosis and aortic calcification in the uremic apolipoprotein E-deficient mouse as an established model of accelerated atherosclerosis.. Female mice were randomly assigned to 4 groups: 2 groups of nonuremic mice (sevelamer versus control) and 2 groups of uremic mice (sevelamer versus control). Sevelamer was given at 3% with chow. The increases in serum phosphorus concentration and calcium-phosphorus product observed in uremic control mice were prevented by sevelamer. Serum total cholesterol was increased in the 2 uremic mouse groups and remained unchanged in response to sevelamer. After 8 weeks of sevelamer treatment, uremic mice exhibited a significantly lower degree of atherosclerosis (P<0.001) and vascular calcification than uremic control mice. Of interest, sevelamer exerted an effect on both intima and media calcification (P=0.005) in uremic mice. Among possible mechanisms involved, we found no evidence for the modulation by sevelamer of inflammation or selected uremic toxins. In contrast, nitrotyrosine staining as a measure of oxidative damage was significantly decreased in response to sevelamer treatment in control and uremic mice (P<0.005).. Sevelamer delays not only vascular calcification but also atherosclerotic lesion progression in uremic apolipoprotein E-deficient mice. It opens the possibility of a cholesterol-independent action of sevelamer on atheroma formation via effects on mineral metabolism, oxidative stress, or both.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Collagen; Disease Progression; Macrophages; Mice; Mice, Knockout; Monocytes; Placebos; Polyamines; Sevelamer; Tyrosine; Uremia