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      The association between atorvastatin administration and plasma total homocysteine levels in renal transplant recipients

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          Abstract

          Background

          Statins improve prognosis in patients with coronary heart diseases by decreasing the incidence of vascular events. Excess prevalence of hyperhomocysteinemia, an independent risk factor of cardiovascular diseases, has been observed in stable renal transplant recipients (RTRs).

          Objectives

          The objective of our study was to evaluate the association between atorvastatin administration and plasma total homocysteine (tHcy) levels in RTRs.

          Patients and Methods

          We performed a retrospective cross-sectional study in 148 cyclosporine A (CsA) treated stable RTRs. We compared tHcy level and other demographic and clinical variables in RTRs with and without atorvastatin.

          Results

          58.1% of the 148 RTRs were treated with atorvastatin (20-40 mg/day). Mean tHcy levels were lower in patients treated with atorvastatin compared to nonusers (14.80 ± 5.13 µmol/l versus 16.95 ± 7.87 µmol/l, P = 0.04). The comparison of 85 patients treated with atorvastatin and 61 non-users revealed that those subjects with atorvastatin were older, with higher estimated creatinine clearance and elevated body mass index (BMI). They were more likely to have higher systolic blood pressure and CsA trough level (C0). The association between lower tHcy levels and atorvastatin use was confirmed in the multivariate regression model ( P = 0.004). However tHcy levels were independently and negatively associated with serum folate ( P = 0.0001) and vitamin B12 levels ( P = 0.001) and positively with serum BUN ( P = 0.001) and diastolic blood pressure ( P = 0.024) as well.

          Conclusions

          These data support the association between lower tHcy levels and atorvastatin administration in RTRs. Further clinical trials are recommended to clarify homocysteine lowering effect of atorvastatin.

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          Most cited references26

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          Strategies to improve long-term outcomes after renal transplantation.

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            Endothelial progenitor cells correlate with endothelial function in patients with coronary artery disease.

            Endothelial progenitor cells (EPC) predict morbidity and mortality in patients at cardiovascular risk.Patients with low EPC counts and impaired endothelial colony forming activity have a higher incidence for cardiovascular events compared to patients with high EPC counts and favorable colony forming activity. The pathophysiological basis for this finding may be an insufficient endothelial cell repair by EPC.We postulate that EPC influence coronary endothelial function which itself is relevant for the outcome of patients at cardiovascular risk. To test this hypothesis in humans, endothelial function was invasively assessed in 90 patients with coronary heart disease by quantitative coronary angiography during intracoronary acetylcholine infusion. Flow cytometry of mononuclear cells isolated from peripheral blood was performed to assess CD133(+) or CD34(+)/KDR(+) EPC. EPC function was assessed ex vivo by determination of endothelial colony forming units. Low EPC number as well as impaired endothelial colony forming activity correlated with severely impaired coronary endothelial function in univariate analysis. Multivariate analysis revealed that only the number of EPC predicts severe endothelial dysfunction independent of classical cardiovascular risk factors. Endothelial function closely correlates with the number of circulating EPC providing new mechanistic insights and options for risk assessment in patients with coronary heart disease.
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              Atorvastatin inhibits homocysteine-induced oxidative stress and apoptosis in endothelial progenitor cells involving Nox4 and p38MAPK.

              Previous studies showed that homocysteine (Hcy) reduces endothelial progenitor cells (EPCs) numbers and impairs functional activity. Atorvastatin, HMG-CoA inhibition has been showed to have protective effects on EPCs. Recent studies have demonstrated that reduced EPCs numbers and activity are associated with EPCs apoptosis. However, the protective mechanisms of atorvastatin on HHcy-induced EPCs apoptosis remain to be determined. This study was designed to examine the effect of atorvastatin on homocysteine-induced reactive oxygen species (ROS) production and apoptosis in EPCs. EPCs were isolated from peripheral blood and characterized, then challenged with Hcy (50-500 micromol/L) in the presence or absence of atorvastatin (0.01-1 micromol/L) or various stress signaling inhibitors, including mevalonate (100 micromol/L), antioxidants N-acetyl cysteine (NAC, 10 micromol/L), the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor diphenylene iodonium (DPI 10 micromol/L), the eNOS inhibitor N(G)mono-methyl-l-arginine LNMA (1mmol/L), and the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580 (10 micromol/L). Apoptosis was evaluated by FACS analysis and cell viability was determined by MTT assay. ROS were detected by 2',7'-dichlorodihydrofluorescein diacetate (H(2)DCFH-DA). NADPH oxidases were evaluated with lucigenin-enhanced chemiluminescence. Expression of Nox4 mRNA and p-p38MAPK protein was measured by RT-PCR and Western blot analysis, respectively. Our data revealed that atorvastatin significantly suppressed Hcy-induced ROS accumulation and EPCs apoptosis. Atorvastatin also antagonized homocysteine-induced activation of NADPH oxidase and overexpression of Nox4 mRNA and p-p38MAPK protein. Similar effects occurred with EPCs transfected with Nox4 siRNA. These findings demonstrated that atorvastatin may inhibit Hcy-induced NADPH oxidase activation, ROS accumulation, and EPCs apoptosis through Nox4/p38MAPK dependent mechanisms, all of which may contribute to atorvastatin-induced beneficial effects on EPCs function. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.
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                Author and article information

                Journal
                J Nephropathol
                J Nephropathol
                J Nephropathol
                J Nephropathol
                JNP
                Journal of Nephropathology
                Society of Diabetic Nephropathy Prevention
                2251-8363
                2251-8819
                July 2016
                07 April 2016
                : 5
                : 3
                : 98-104
                Affiliations
                Urology Research Center, Guilan University of Medical Sciences, Guilan, Iran
                Author notes
                [* ] Corresponding author: Seyyede Zeinab Azimi, Department of Nephrology, Razi Hospital, Urology Research Center, Guilan University of Medical Sciences, Guilan, Iran sz.azimi@ 123456yahoo.com
                Article
                10.15171/jnp.2016.18
                4961823
                27540537
                d85bac0d-8564-4b2e-921b-946db1e6faa0
                © 2016 The Author(s)

                Published by Society of Diabetic Nephropathy Prevention. This is an open-access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 29 January 2016
                : 19 March 2016
                Page count
                Tables: 5, References: 29, Pages: 7
                Categories
                Original Article

                homocysteine,atorvastatin,transplantation,renal,transplant recipients

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