losartan-potassium and Atherosclerosis

Erythropoiesis-stimulating agents (ESA) are used to treat renal anemia. The TREAT study (Trial to Reduce Cardiovascular Events with Aranesp Ther- apy) of diabetic patients with chronic kidney disease (CKD) found that the risk of stroke was significantly higher than in the control arm. This raises the question as to what causes this phenomenon. Platelets may play a crucial role in this context. Atherogenesis involves complex interactions between platelets and monocytes (platelet-monocyte crosstalk) and with endothelial cells. Platelets are activated in cases of diabetes mellitus, especially. During atherogenesis, partial functions of platelets other than those inhibited by aspirin, as a cyclooxygenase inhibitor, or by adenosine diphosphate receptor P2Y(12)antagonists, such as thienopyridines, are of relevance. During platelet-monocyte crosstalk, specifically, an important role is played by adhesion receptors such as selectins and integrins. In addition, ESA cause platelet activation by direct and indirect mechanisms. Antagonistic thereto is a renal bleeding tendency in cases of severe CKD, due to platelet dysfunction, which can be remedied with appropriate renal replacement therapy and administration of ESA in order to reach a hemoglobin (Hb) level of 10 g/dl. However, if the Hb level exceeds 10 g/dl, the even stronger platelet activation caused by ESA, combined with the activation caused by diabetes, leads to a prothrombotic state, which in patients with severe atherosclerosis can result in acute atherothrombotic complications, in the genesis of which platelets play a key role. This would be one hypothesis for explaining the increased incidence of strokes in the TREAT study.

Topics: Anemia; Atherosclerosis; Blood Platelets; Darbepoetin alfa; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Erythropoietin; Female; Hematinics; Hemoglobinometry; Humans; Integrins; Intracranial Embolism; Male; Monocytes; Platelet Activation; Randomized Controlled Trials as Topic; Receptor Cross-Talk; Renal Replacement Therapy; Selectins

Endothelial injury is thought to play a pivotal role in the development and progression of vascular diseases, such as atherosclerosis, hypertension or restenosis, as well as their complications, including myocardial infarction or stroke. Accumulating evidence suggests that bone marrow-derived endothelial progenitor cells (EPCs) promote endothelial repair and contribute to ischemia-induced neovascularization. Coronary artery disease and its risk factors, such as diabetes, hypercholesterolemia, hypertension and smoking, are associated with a reduced number and impaired functional activity of circulating EPCs. Moreover, initial data suggest that reduced EPC levels are associated with endothelial dysfunction and an increased risk of cardiovascular events, compatible with the concept that impaired EPC-mediated vascular repair promotes progression of vascular disease. In this review we summarize recent data on the effects of pharmacological agents on mobilization and functional activity of EPCs. In particular, several experimental and clinical studies have suggested that statins, angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, PPAR-gamma agonists and erythropoietin increase the number and functional activity of EPCs. The underlying mechanisms remain largely to be defined; however, they likely include activation of the PI3-kinase/Akt pathway and endothelial nitric oxide synthase, as well as inhibition of NAD(P)H oxidase activity of progenitor cells.

Topics: AC133 Antigen; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antigens, CD; Antigens, CD34; Atherosclerosis; Benzopyrans; Carbazoles; Cardiovascular Diseases; Carvedilol; Cell Differentiation; Coronary Disease; Endothelium, Vascular; Erythropoietin; Ethanolamines; Glycoproteins; Hematopoietic Stem Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Insulin; Nebivolol; Neovascularization, Physiologic; Oxidative Stress; Peptides; PPAR gamma; Propanolamines; Receptors, Angiotensin; Regeneration; Risk Factors; Rosiglitazone; Stem Cells; Thiazolidinediones; Vasodilator Agents

New concepts in the field of atherothrombosis include the human potential to repair and regenerate areas of vascular damage through endogenous growth factors, and the identification of uncommon arterial thrombophilias that promote atherothrombosis. The endogenous factors erythropoietin and insulin-like growth factor-1 are emerging as robust opponents of the vascular and hemostatic alterations that occur in atherothrombosis. Both factors activate the intracellular Akt pathway and the biosynthesis of constitutive nitric oxide, with anti-apoptotic, insulin-sensitizing, vasodilator, anti-inflammatory, antioxidant and antiplatelet effects, all of which oppose arterial degeneration and occlusion. Additionally, erythropoietin and insulin-like growth factor-1 induce the mobilization of stem cells that can differentiate and repair areas of vascular damage thereby halting the progression towards established disease. In selected patients with an arterial thrombotic event, we believe it is justified to search for an uncommon acquired or inherited thrombophilic condition in the presence of at least one of the following: young age, recurrent events, lack of traditional metabolic or acquired vascular risk factors, and no significant artery stenoses at angiography. In these groups of patients, and in those with a marked family history of thrombosis, the prevalence of several functional polymorphisms of genes involved in the hemostatic system is significantly higher compared with controls. Acquired thrombophilias that should be searched for include the antiphospholipid syndrome, systemic lupus erythematosus, and myeloproliferative disorders.

Topics: Atherosclerosis; Biomarkers; Coronary Thrombosis; Erythropoietin; Humans; Insulin-Like Growth Factor I; Intracranial Thrombosis; Nitric Oxide; Risk Factors; Stem Cells; Thrombophilia

Atherosclerotic renal artery stenosis (ARAS) is common in cardiovascular diseases and associated with hypertension, renal dysfunction and/or heart failure. There is a paucity of data about the prevalence and the role of ARAS in the pathophysiology of combined chronic heart failure (CHF) and chronic kidney disease (CKD). We investigated the prevalence in patients with combined CHF/CKD and its association with renal function, cardiac dysfunction and the presence and extent of myocardial fibrosis.. The EPOCARES study (ClinTrialsNCT00356733) investigates the role of erythropoietin in anaemic patients with combined CHF/CKD. Eligible subjects underwent combined cardiac magnetic resonance imaging (cMRI), including late gadolinium enhancement, with magnetic resonance angiography of the renal arteries (MRA).. MR study was performed in 37 patients (median age 74 years, eGFR 37.4 ± 15.6 ml/min, left ventricular ejection fraction (LVEF) 43.3 ± 11.2%), of which 21 (56.8%) had ARAS (defined as stenosis >50%). Of these 21 subjects, 8 (21.6%) had more severe ARAS >70% and 8 (21.6%) had a bilateral ARAS >50% (or previous bilateral PTA). There were no differences in age, NT-proBNP levels and medication profile between patients with ARAS versus those without. Renal function declined with the severity of ARAS (p = 0.03), although this was not significantly different between patients with ARAS versus those without. Diabetes mellitus was more prevalent in patients without ARAS (56.3%) against those with ARAS (23.8%) (p = 0.04). The presence and extent of late gadolinium enhancement, depicting myocardial fibrosis, did not differ (p = 0.80), nor did end diastolic volume (p = 0.60), left ventricular mass index (p = 0.11) or LVEF (p = 0.15). Neither was there a difference in the presence of an ischemic pattern of late enhancement in patients with ARAS versus those without.. ARAS is prevalent in combined CHF/CKD and its severity is associated with a decline in renal function. However, its presence does not correlate with a worse LVEF, a higher left ventricular mass or with the presence and extent of myocardial fibrosis. Further research is required for the role of ARAS in the pathophysiology of combined chronic heart and renal failure.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Atherosclerosis; Cardio-Renal Syndrome; Chi-Square Distribution; Contrast Media; Erythropoietin; Female; Fibrosis; Glomerular Filtration Rate; Heart Failure; Hematinics; Humans; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Male; Meglumine; Middle Aged; Myocardium; Netherlands; Organometallic Compounds; Predictive Value of Tests; Prevalence; Prognosis; Renal Artery; Renal Artery Obstruction; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; Severity of Illness Index; Stroke Volume; Ventricular Function, Left

Erythropoietin (EPO) has been widely used for the treatment of anemia in chronic kidney disease (CKD). A growing body of evidence indicates that the therapeutic benefits of EPO could extend beyond the improvement of anemia. The aim of the present study was to determine whether EPO affects renovascular and oxidative stress biomarkers in pre-dialysis CKD patients with anemia.. The study was a single-arm prospective study. Fifteen CKD patients (9 males and 6 females, mean age 63 years) with anemia (mean Hb: 8.1 g/dL) were treated with recombinant human EPO; 12,000 U administered subcutaneously once every 2 weeks. Various parameters were measured before and 6 months after treatment. These included serum hemoglobin (Hb), creatinine, estimated glomerular filtration rate (eGFR), proteinuria, urinary liver-type fatty acid binding protein (L-FABP--a biomarker of renal injury), urinary 8-hydroxydeoxyguanosine (8-OHdG--a marker of oxidative stress), serum asymmetrical dimethylarginine (ADMA), carotid artery intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV) as vascular markers and plasma brain natriuretic peptide (BNP) levels and left ventricular ejection fraction (LVEF) as cardiac function markers and cardio-thoracic ratio (CTR) and inferior vena cava dimension (IVCS) as extra fluid retention markers.. After 6 months, serum Hb was significantly increased (p<0.001) and urinary levels of protein, L-FABP and 8-OHdG, carotid IMT, baPWV, plasma BNP and serum ADMA levels were significantly decreased (p<0.001). Serum creatinine, eGFR, LVEF, CTR and IVCS showed little difference throughout the experimental period.. These data suggest that recombinant human EPO may ameliorate renal injury, oxidative stress and progression of atherosclerosis in addition to improving anemia in CKD patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute Kidney Injury; Aged; Arginine; Atherosclerosis; Biomarkers; Cardiovascular System; Carotid Intima-Media Thickness; Deoxyguanosine; Dose-Response Relationship, Drug; Erythropoietin; Fatty Acid-Binding Proteins; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Natriuretic Peptide, Brain; Oxidative Stress; Prospective Studies; Recombinant Proteins; Treatment Outcome

Mortality in dialysis patients remains high and is due mainly to cardiovascular causes. Inflammation has a role in the genesis of accelerated atherosclerosis, vascular calcification, malnutrition and anemia, and a huge impact on the survival of these patients. The pleiotropic effects of statins can be a therapeutic option for reducing chronic inflammatory processes of patients undergoing hemodialysis.. To evaluate the effects of low doses of simvastatin on inflammatory markers, hematimetric and nutritional parameters of patients undergoing hemodialysis.. Clinically-stable patients undergoing hemodialysis were classified according to their baseline LDL-cholesterol levels in two groups: those with levels below 100mg/dl (Group 1) and those with levels equal to or greater than 100mg/dl (Group-2), and were treated with simvastatin during eight weeks. Group 1 received 20mg only after each session of hemodialysis (intermittent dose), whereas Group 2 received 20mg/daily. Laboratory data, erythropoietin resistance index and nutritional parameters were obtained before and after treatment.. A significant and equivalent reduction in C-reactive protein levels in both groups was observed (35.97+/-49.23% vs 38.32+/-32.69%, p=0.86). In group 1, there was also a tendency towards reduced resistance to erythropoietin (228.6+/-16.2 vs 208.9+/-16.2, p=0.058) and improvement of hematimetric parameters (hematocrit: 33.1+/-5.9% vs 36.1+/-4.5%, p=0.021).. Intermittent doses proved to be as effective as the usual dose in reducing C-reactive protein levels and resistance to erythropoietin, besides improving the hematimetric parameters, indicating an important reduction of the cardiovascular risk evaluated by these parameters.

Topics: Adult; Aged; Anemia; Anticholesteremic Agents; Atherosclerosis; Biomarkers; C-Reactive Protein; Cholesterol, LDL; Drug Resistance; Erythropoietin; Female; Hemoglobins; Humans; Male; Malnutrition; Middle Aged; Nutritional Status; Prospective Studies; Renal Dialysis; Simvastatin; Young Adult

This study aimed to investigate role of erythropoietin in atherosclerosis and explore whether underlying mechanism is associated with PI3K/AKT/mTOR pathway.. High-fat-diet-induced atherosclerosis model was established in apolipoprotein E knockout mice (C57BL/6 genetic background). Mice were randomly divided into the control group and the EPO group. Hematoxylin-eosin was performed for the determination of atherosclerotic lesions. The expression levels of related proteins were detected by western blot analysis.. Erythropoietin significantly enhanced the incidence of hemorrhage in atherosclerotic plaques compared with the control group. The proteins' expression signaling pathways (including PI3K, AKT, and mTOR) and angiogenesis-related proteins (VEGF, COX-2, and HIF-1α) were proved to be up-regulated by erythropoietin. Additionally, erythropoietin significantly enhanced the incidence of hemorrhage in the atherosclerotic plaques compared with the control group. The vitro experiments were conducted in macrophages at 21% O. The present study demonstrated that erythropoietin might promote angiogenesis in atherosclerotic vulnerable by activating PI3K/AKT/mTOR signaling pathway in atherosclerotic, providing a novel therapeutic target for atherosclerotic targeted therapy.

Topics: Animals; Atherosclerosis; Cyclooxygenase 2; Erythropoietin; Mice; Mice, Inbred C57BL; Phosphatidylinositol 3-Kinases; Plaque, Atherosclerotic; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Cardiovascular morbidity and mortality is very important in patients with chronic renal failure. This occurs even in mild impairment of renal function and may be related to oxidative stress and chronic inflammation. The nephrectomized apo E knockout mouse is an accepted model for evaluating atherosclerosis in renal dysfunction. Erythropoietin derivates showed anti-oxidative and anti-inflammatory effects. Therefore, this study evaluates the effects of Darbepoetin on markers of oxidative stress and chronic inflammation in atherosclerotic lesions in apo E knockout mice with renal dysfunction.. Apo E knockout mice underwent unilateral (Unx, n = 20) or subtotal (Snx, n = 26) nephrectomy or sham operation (Sham, n = 16). Mice of each group were either treated with Darbepoetin or saline solution, a part of Snx mice received a tenfold higher dose of Darbepoetin. The aortic plaques were measured and morphologically characterized. Additional immunhistochemical analyses were performed on tissue samples taken from the heart and the aorta.. Both Unx and Snx mice showed increased expression of markers of oxidative stress and chronic inflammation. While aortic plaque size was not different, Snx mice showed advanced plaque stages when compared to Unx mice. Darbepoetin treatment elevated hematocrit and lowered Nitrotyrosin as one marker of oxidative stress, inflammation in heart and aorta, plaque stage and in the high dose even plaque cholesterol content. In contrast, there was no influence of Darbepoetin on aortic plaque size; high dose Darbepoetin treatment resulted in elevated renal serum parameters.. Darbepoetin showed some protective cardiovascular effects irrespective of renal function, i.e. it improved plaque structure and reduced some signs of oxidative stress and chronic inflammation without affecting plaque size. Nevertheless, the dose dependent adverse effects must be considered as high Darbepoetin treatment elevated serum urea. Elevation of hematocrit might be a favorable effect in anemic Snx animals but a thrombogenic risk in Sham animals.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Darbepoetin alfa; Erythropoietin; Inflammation; Mice; Mice, Knockout; Oxidative Stress; Renal Insufficiency

To investigate the mechanisms of Porphyromonas gingivalis (Pg) infection-mediated enhancement of adhesion between monocytes THP-1 and human umbilical vein endothelial cells (HUVEC) by detecting the effect of erythropoietin producing hepatomocellular receptor interacting protein B2 (Ephrin B2) and its receptors on the adhesion.. PgATCC33277 was cultured in an anaerobic jar, and THP-1 cells were infected with various concentrations of Pg at multiplicity of infection (MOI) of 1:100 for 8 and 24 h, respectively. The expression of Ephrin B2 receptor of THP-1 cells was detected. After removal of the free Pg, THP-1 cells were cocultured with HUVEC (overexpress of EphrinB2 or not) for 24 h to detect the expression of Ephrin B2 of HUVEC cells after additional cultivation for 23 h.. The adhesion of THP-1 cells post infection by Pg to HUVEC was enhanced. The mRNA levels of Ephrin B2 receptors, including EphB3 (5.169±0.152, P = 0.005), EphB4 (11.040±1.195, P = 0.001), and EphA4 (4.976± 0.122, P = 0.001) expressed by THP-1, and Ephrin B2 (8.938±0.962, P = 0.008) expressed by HUVEC were significantly elevated 24 h post infection of Pg. Over expression of Ephrin B2 in HUVEC promoted the adhesion of THP-1 to HUVEC.. Ephrin B2 and its receptors are involved in Pg infection mediated enhancement of the adhesion of THP-1 to HUVEC cells, suggesting that Ephrin B2 participates in the development of atherosclerosis.

Topics: Atherosclerosis; Cell Adhesion; Cells, Cultured; Coculture Techniques; Endothelium, Vascular; Ephrin-B2; Epoetin Alfa; Erythropoietin; Human Umbilical Vein Endothelial Cells; Humans; Monocytes; Porphyromonas gingivalis; Recombinant Proteins; Umbilical Veins

This study aimed to explore the relationship between recombinant human erythropoietin (EPO) responsiveness, insulin resistance, and malnutrition-inflammation-atherosclerosis (MIA) syndrome in hemodialysis patients.. This was an observational cohort study in hemodialysis patients. Adipokines, inflammatory cytokines, and required EPO dosage were measured in diabetes (DM; n=58) and non-diabetes (non-DM; n=58) groups over 48 weeks. Furthermore, the EPO responsiveness index (required EPO dosage divided by hemoglobin) was evaluated with or without MIA syndrome in both groups.. The DM group had significantly higher plasma leptin, interleukin-6 (IL-6), and high sensitivity C-reactive protein (hs-CRP) levels but lower plasma high molecular weight (HMW) adiponectin levels compared to the non-DM group. Although hemoglobin levels were not significantly different, required EPO dosage was significantly higher in the DM group than in the non-DM group, particularly in the presence of MIA syndrome. The DM group with MIA syndrome had significantly higher plasma leptin, IL-6, and hs-CRP levels but lower plasma HMW adiponectin levels compared to the non-DM group with MIA syndrome. There was also a significant association between EPO dosage and homeostasis model assessment for insulin resistance (HOMA-IR), hs-CRP, IL-6, tumor necrosis factor a, leptin, and HMW adiponectin levels in DM patients with MIA syndrome.. Diabetic hemodialysis patients with MIA syndrome have a lower response to EPO and a higher resistance to insulin. This fact may explain the poor outcome of these patients and demonstrate the importance of diagnosis and therapeutic management.

Topics: Aged; Analysis of Variance; Anemia; Atherosclerosis; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Erythropoietin; Female; Glycated Hemoglobin; Hematinics; Humans; Inflammation; Inflammation Mediators; Insulin Resistance; Japan; Kidney Failure, Chronic; Lipids; Male; Malnutrition; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Syndrome; Time Factors; Treatment Outcome

The purpose of this study was to focus on pathophysiological mechanisms linking β-thalassemia intermedia (β-TI) and minor (β-TMI) with cardiovascular risk. Iron status, prooxidant-antioxidant balance and lipid profiles in serum, and lipid content in peripheral blood mononuclear cells (PBMCs) were evaluated in 20 β-TMI subjects, 22 β-TI patients and in 30 nonthalassemic blood donors. The mRNA levels of some genes involved in the regulation of iron and cholesterol metabolism were also determined. In β-TI and in β-TMI, serum iron, prooxidant-antioxidant ratio, transferrin saturation and erythropoietin levels were higher, while transferrin and hepcidin were lower compared to controls. Hepcidin and interleukin-1α mRNA levels were found to be reduced in β-TI- and β-TMI-PBMCs, while those of tumor necrosis factor alpha were increased. A reduction in high-density lipoprotein cholesterol in serum and an accumulation of neutral lipids coupled with increased mRNA levels of acetyl-coenzyme A:cholesterol acyltransferase and decreased neutral cholesterol ester hydrolase in PBMCs were also observed in β-TI and β-TMI compared to controls. Taken together, these findings provide experimental support for the idea that not only β-TI patients but also β-TMI have a proatherogenic biochemical phenotype which may contribute to increase their cardiovascular disease risk.

Topics: Acetyl-CoA C-Acetyltransferase; Adult; Antimicrobial Cationic Peptides; Atherosclerosis; beta-Thalassemia; Cholesterol, HDL; Erythropoietin; Female; Hepcidins; Humans; Interleukin-1alpha; Iron; Italy; Leukocytes, Mononuclear; Male; Middle Aged; Oxidative Stress; Phenotype; Risk Factors; RNA, Messenger; Severity of Illness Index; Sterol Esterase; Transferrin; Tumor Necrosis Factor-alpha

It is not clear why cardiac or renal cachexia in chronic diseases is associated with poor cardiovascular outcomes. Platelet reactivity predisposes to thromboembolic events in the setting of atherosclerotic cardiovascular disease, which is often present in patients with end-stage renal disease (ESRD).. We hypothesized that ESRD patients with relative thrombocytosis (platelet count >300 × 10(3)/μL) have a higher mortality rate and that this association may be related to malnutrition-inflammation cachexia syndrome (MICS).. We examined the associations of 3-mo-averaged platelet counts with markers of MICS and 6-y all-cause and cardiovascular mortality (2001-2007) in a cohort of 40,797 patients who were receiving maintenance hemodialysis.. The patients comprised 46% women and 34% African Americans, and 46% of the patients had diabetes. The 3-mo-averaged platelet count was 229 ± 78 × 10(3)/μL. In unadjusted and case-mix adjusted models, lower values of albumin, creatinine, protein intake, hemoglobin, and dialysis dose and a higher erythropoietin dose were associated with a higher platelet count. Compared with patients with a platelet count of between 150 and 200 × 10(3)/μL (reference), the all-cause (and cardiovascular) mortality rate with platelet counts between 300 and <350, between 350 and <400, and ≥400 ×10(3)/μL were 6% (and 7%), 17% (and 15%), and 24% (and 25%) higher (P < 0.05), respectively. The associations persisted after control for case-mix adjustment, but adjustment for MICS abolished them.. Relative thrombocytosis is associated with a worse MICS profile, a lower dialysis dose, and higher all-cause and cardiovascular disease death risk in hemodialysis patients; and its all-cause and cardiovascular mortality predictability is accounted for by MICS. The role of platelet activation in cachexia-associated mortality warrants additional studies.

Topics: Adult; Aged; Albumins; Atherosclerosis; Black or African American; Cachexia; Cause of Death; Cohort Studies; Creatinine; Diabetes Mellitus; Dialysis; Dietary Proteins; Erythropoietin; Female; Hemoglobins; Humans; Inflammation; Kidney Failure, Chronic; Male; Malnutrition; Middle Aged; Platelet Count; Prevalence; Thrombocytosis

Narrowing of the arteries due to atherosclerosis may lead to congestive heart failure (CHF). It is advantageous to perform atherosclerosis studies in apolipoprotein E-deficient (Apo E(-/-)) mice models, which develop atherosclerosis very rapidly in comparison to humans. Darbepoetin is a synthetic erythropoietin analogue and stimulates erythropoiesis. The aim of this study was to explore the effect of 16 weeks of darbepoetin treatment on serum protein profiles in Apo E(-/-) mice during atherosclerosis progression. Serum proteomic analyses were performed using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) in the darbepoetin-treated and non-treated (control) Apo E(-/-) mice groups. The protein profiles obtained using three different chips, CM-10 (weak cation exchange), H50 (reversed-phase) and IMAC-30 (immobilized metal affinity capture), were statistically analyzed using the ProteinChip data manager 3.0 program. At the end of 16 weeks of darbepoetin treatment, there was no significant difference in the size and degree of atherosclerotic lesions between the darbepoetin and control mice groups. In contrast, 145 protein/peptide-clustering peaks, >5 kDa, had statistically significant differences in their peak intensities between the darbepoetin and control mice groups (p<0.05). That the proteomic profiles of darbepoetin-treated Apo E(-/-) mice were found to differ from those of the control group indicates a potential beneficial role of darbepoetin in atherosclerosis. Our study contributes to understanding the effects of darbepoetin on protein/peptide expressions during atherosclerosis development.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Blood Proteins; Body Weight; Darbepoetin alfa; Down-Regulation; Erythropoietin; Gene Expression; Hematinics; Male; Mice; Mice, Knockout; Molecular Weight; Plaque, Atherosclerotic; Protein Array Analysis; Proteomics; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Up-Regulation

Anemia is a common but often overlooked complication of diabetes. We investigated the relationship between hemoglobin concentration and various factors as well as markers of subclinical atherosclerosis in men with type 2 diabetes mellitus. Hemoglobin concentration was measured in 319 men with type 2 diabetes mellitus. We evaluated the relationship between hemoglobin concentration and various factors including age, body mass index, and glycemic control, as well as between hemoglobin concentration and pulse wave velocity or ankle-brachial index (n = 209) and between hemoglobin concentration and carotid intima-media thickness or plaque score (n = 125). Mean hemoglobin concentration was 14.2 +/- 0.80 g/dL. Body mass index (r = 0.340, P < .0001) and estimated glomerular filtration rate (r = 0.219, P = .0011) were positively associated with hemoglobin concentration, whereas age (r = -0.388, P < .0001), glycated albumin (r = -0.148, P = .0121), serum creatinine concentration (r = -0.206, P = .0019), and log (urinary albumin excretion) (r = -0.188, P = .0010) were negatively associated with hemoglobin concentration. Multiple regression analysis identified age (beta = -0.222, P = .0019), body mass index (beta = 0.145, P = .0432), systolic blood pressure (beta = 0.214, P = .0015), total cholesterol concentration (beta = 0.170, P = .0077), and serum creatinine concentration (beta = -0.181, P = .0045) as independent determinants of hemoglobin concentration. No significant association was observed between hemoglobin concentration and serum erythropoietin concentration (r = -0.079, P = .2980). Negative correlations were found between hemoglobin concentration and pulse wave velocity (r = -0.289, P < .0001) and between hemoglobin concentration and plaque score (r = -0.275, P = .0024). In conclusion, hemoglobin concentration was associated with various factors; and decreased hemoglobin concentration was associated with subclinical markers of atherosclerosis in men with type 2 diabetes mellitus.

Topics: Age Factors; Aged; Ankle Brachial Index; Atherosclerosis; Blood Glucose; Blood Pressure; Body Mass Index; Carotid Arteries; Creatinine; Diabetes Mellitus, Type 2; Erythropoietin; Hemoglobins; Humans; Male; Middle Aged; Regression Analysis; Ultrasonography

In addition to the hematopoietic effect of erythropoietin, increasing evidence suggests that erythropoietin also exerts protective effects for cardiovascular diseases. However, the role of erythropoietin and its underlying mechanism in macrophage foam cell formation are poorly understood.. Compared with wild-type specimens, erythropoietin was increased in atherosclerotic aortas of apolipoprotein E-deficient (apoE(-/-)) mice, mainly in the macrophage foam cells of the lesions. Erythropoietin levels in culture medium and macrophages were significantly elevated in response to oxidized low-density lipoprotein in a dose-dependent manner. Furthermore, erythropoietin markedly attenuated lipid accumulation in oxidized low-density lipoprotein-treated macrophages, a result that was due to an increase in cholesterol efflux. Erythropoietin treatment significantly increased ATP-binding cassette transporters (ABC) A1 and ABCG1 mRNA and protein levels without affecting protein expression of scavenger receptors, including scavenger receptor-A, CD36, and scavenger receptor-BI. The upregulation of ABCA1 and ABCG1 by erythropoietin resulted from liver X receptor alpha activation, which was confirmed by its prevention on expression of ABCA1 and ABCG1 after pharmacological or small interfering RNA inhibition of liver X receptor alpha. Moreover, the erythropoietin-mediated attenuation on lipid accumulation was abolished by such inhibition. Finally, reduced lipid accumulation and marked increase in ABCA1 and ABCG1 were demonstrated in erythropoietin-overexpressed macrophages.. Our data suggest that erythropoietin suppresses foam cell formation via the liver X receptor alpha-dependent upregulation of ABCA1 and ABCG1.

Topics: Animals; Aortic Diseases; Apolipoproteins E; Atherosclerosis; ATP Binding Cassette Transporter 1; ATP Binding Cassette Transporter, Subfamily G, Member 1; ATP-Binding Cassette Transporters; Cardiotonic Agents; CD36 Antigens; Cells, Cultured; Erythropoietin; Foam Cells; Lipids; Lipoproteins; Lipoproteins, LDL; Liver X Receptors; Mice; Mice, Inbred C57BL; Mice, Transgenic; Orphan Nuclear Receptors; RNA, Messenger; Scavenger Receptors, Class A; Scavenger Receptors, Class B

End-stage renal disease (ESRD) patients treated by haemodialysis (HD) have impaired endothelium-dependent vasodilatation and increased intima-media thickness (IMT) of the carotid artery The aim of the study was to analyse the relationships between parameters of chronic HD treatment and non-invasive assessments of preclinical atherosclerosis (endothelial dysfunction and carotid IMT) in ESRD patients on HD.. Fifty-two (19 females, 33 males) adult patients on chronic maintenance (4.65 +/- 3.29 years) HD aged 59.88 +/- 15.49 years were investigated. Ultrasonographic studies were performed with a 7.5 MHz high-resolution probe. The common carotid artery IMT was measured. Brachial artery diameter was analysed to the rest. In order to assess flow-mediated dilatation (FMD), hyperaemia was induced by a pneumatic cuff, and an analysis of the diameter was performed 1, 2, 3 and 4 min after cuff deflation.. Significant differences were found in the average carotid IMT value between subjects with delivered dialysis dose (Kt/V) > or =1.2 and <1.2 (0.89 +/- 0.21 vs 1.04 +/- 0.11, P = 0.0045). A correlation between Kt/V and IMT (r = 0.366, P = 0.004) was demonstrated. FMD values of the brachial artery did not correlate with Kt/V. A correlation between low molecular weight heparin per kg of body mass and maximal percent of FMD was demonstrated (r = -0.242, P = 0.049). The maximal percent of brachial FMD was correlated with absolute difference between pre- and postdialysis pulse pressure values (r = -0.265, P = 0.033). In a partial correlation with haemoglobin as control, a variable significant correlation between total erythropoietin dose and maximal carotid IMT (r = -0.262, P = 0.036) was found. In a multiple linear regression model, Kt/V was independently correlated with carotid IMT values (beta = -0.227, P = 0.0335).. This study has demonstrated the association between HD procedure and early atherosclerosis markers. HD treatment has to be considered as potential modifying factor in atherosclerosis development.

Topics: Adult; Aged; Aged, 80 and over; Atherosclerosis; Biomarkers; Carotid Arteries; Cross-Sectional Studies; Endothelium, Vascular; Erythropoietin; Female; Humans; Linear Models; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Tunica Intima; Tunica Media

Patients with advanced chronic renal disease (CRD) suffer from excessive morbidity and mortality due to complications of accelerated atherosclerosis. Approximately 90% of dialysis-dependent end stage renal disease patients suffer from anemia. Recombinant human erythropoietin (EPO) in combination with iron has become widely used to treat anemic CRD patients. While treatment with EPO results in improved quality of life it may also contribute to the development of atherosclerosis. Recent studies suggest that a reduction in nitric oxide (NO) availability may be linked to EPO-induced vascular dysfunction. Furthermore, CRD per se is thought to result in a state of NO deficiency. The present study suggests that EPO may exert proatherogenic activity by augmenting the cytokine-induced expression of monocyte-chemoattractant protein-1 (MCP-1) in human umbilical vein endothelial cells (HUVECs) and by stimulating the proliferation of HUVECs and human vascular smooth muscle cells (HVSMCs). Augmentation of MCP-1 expression appears to be linked to EPO-induced downregulation of endothelial NO synthase (ecNOS). NO released from a series of synthetic donor compounds suppressed the EPO-mediated augmentation of cytokine-induced MCP-1 expression. In vitro studies revealed that EPO reduces ecNOS expression at both the protein and mRNA levels and that EPO also mediates a reduction in ecNOS enzymatic activity. These observations suggest potential mechanisms through which EPO may contribute to the development of accelerated atherosclerosis, particularly in the setting of CRD where NO availability may already be compromised.

Topics: Atherosclerosis; Cell Proliferation; Cells, Cultured; Chemokine CCL2; Down-Regulation; Endothelial Cells; Endothelium, Vascular; Erythropoietin; Humans; Kidney Failure, Chronic; Myocytes, Smooth Muscle; NF-kappa B; Nitric Oxide; Recombinant Proteins; RNA, Messenger

CC-chemokines are now widely accepted in the recruitment of leukocytes from the blood compartment into tissues, and their role in the progression of atherosclerosis has been documented. Recombinant human erythropoietin (EPO) has become widely used to treat anemic HD patients. However, little is known about the effect of EPO on the plasma CC-chemokine levels and intima-media thickness (IMT) in HD patients.. Assessment of CC-chemokines: monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory proteins (MIP-1alpha, MIP-1beta), regulated upon activation, normal T cell expressed and secreted (RANTES) and IMT were performed in 26 stable HD patients and 15 healthy controls. The patients were divided into 3 groups: group I (n = 8, without EPO), group II (n = 9, EPO at a mean dose of 76 +/- 48 U/kg/week for more than 4 months), and group III (n = 9, EPO at a mean dose of 110.5 +/- 21 U/kg/week for more than 12 months), none of them on iron therapy.. MCP-1, MIP-1alpha, MIP-1beta and IMT values were significantly higher, whereas RANTES were significantly lower in HD patients without EPO therapy than those in healthy controls. CC-chemokine levels were found to be significantly lower in patients administered EPO when compared to subjects without EPO. In the patients treated with EPO for more than 12 months IMT values were significantly decreased compared to patients not receiving this hormone.. These results suggest that long-term EPO therapy decreased CC-chemokine and IMT values in patients undergoing regular HD in the absence of concomitant iron supplementation.

Topics: Atherosclerosis; Carotid Arteries; Chemokines, CC; Erythropoietin; Female; Humans; Male; Middle Aged; Renal Dialysis; Tunica Intima; Tunica Media; Uremia