losartan-potassium and Vascular-Diseases

Recombinant human erythropoietin (rhEPO) is used in breast and ovarian cancer patients to alleviate cancer- and chemotherapy-related anemia. Some clinical trials have reported that rhEPO may adversely impact survival and increase the risk of thrombovascular events in patients with breast cancer but not with ovarian cancer. The latter may potentially benefit the most from rhEPO treatment due to the nephrotoxic and myelosuppresive effects of standard platinum-based chemotherapy used in ovarian cancer disease. However, over the last decade the preclinical data have revealed that EPO is not only the principal growth factor and the hormone which regulates erythropoiesis, but also a cytokine with a pleiotropic activity which also can affect cancer cells. EPO can stimulate survival, ability to form metastases and drug resistance not only in continuous breast- and ovarian cancer cell lines but also in breast cancer stem-like cells. EPO receptor (EPOR) can also be constitutively active in both these cancers and, in breast cancer cells, may act in an interaction with estrogen receptor (ER) and epidermal growth factor receptor-2 (HER-2). EPOR, by an EPO-independent mechanism, promotes proliferation of breast cancer cells in cooperation with estrogen receptor, resulting in decreased effectiveness of tamoxifen treatment. In another interaction, as a result of the molecular antagonism between EPOR and HER2, rhEPO protects breast cancer cells against trastuzumab. Both clinical and preclinical evidence strongly suggest the urgent need to reevaluate the traditional use of rhEPO in the oncology setting.

Topics: Antineoplastic Agents; Breast Neoplasms; Drug Resistance; Erythropoietin; Female; Humans; Ovarian Neoplasms; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction; Vascular Diseases

Topics: Adaptation, Physiological; Altitude Sickness; Calcium; Chronic Disease; Endothelium, Vascular; Erythropoietin; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Hypoxia; Muscle, Smooth; Pulmonary Edema; Vascular Diseases; Vascular Remodeling; Vasoconstriction

Cytokine and growth factor--erythropoietin (EPO)--apart from it's hematopoietic function is now considered to be a cytoprotective agent in a variety of vascular diseases, nervous system disorders and metabolic impairments. Recent work has elucidated that erythropoietin controls a variety of signal transduction pathways involving Janus-tyrosine kinase 2, protein kinase B, signal transducer and activator of transcription, Wnt proteins, forkhead transcription factors, caspases, and nuclear factor kappaB. Further investigations of cellular pathways controlled by erythropoietin can be the base for therapeutic applicability of this cytokine throughout the body.

Topics: Animals; Cytoprotection; Erythropoietin; Humans; Janus Kinase 2; Metabolic Diseases; Nervous System Diseases; Protein Binding; Proto-Oncogene Proteins c-akt; Signal Transduction; TYK2 Kinase; Vascular Diseases

The major physiological function of erythropoietin (EPO) is thought to be the induction of erythropoiesis. However, a growing body of evidence indicates that EPO as well as recombinant human erythropoietin (rHuEPO) and its analogues have tissue-protective effects and prevent tissue damage during ischaemia. This mini review summarizes the present knowledge on protective vascular effects of EPO and discusses the potential underlying mechanisms.

Topics: Cell Differentiation; Endothelial Cells; Endothelium; Erythropoietin; Humans; Nitric Oxide; Protein Serine-Threonine Kinases; Receptors, Erythropoietin; Signal Transduction; Vascular Diseases

The well-established physiological function of erythropoietin (EPO) is the induction of erythropoiesis. A growing body of evidence indicates that EPO has tissue-protective effects and prevents tissue damage during ischemia and inflammation. Tissue protection after ischemia and injury has been found in the brain, heart, and kidney. It has been speculated that EPO has anti-apoptotic effects in cardiovascular cells. These novel effects of EPO seem to be independent of its erythropoietic activity. Unclear is the role of the known EPO receptor or whether other signaling pathways are involved; a novel EPO receptor might be involved in tissue protection by this hormone. This review article summarizes present knowledge of cardiovascular and renal protective effects of EPO and discusses possible underlying mechanisms.

Topics: Acute Kidney Injury; Anemia; Animals; Cardiovascular Diseases; Erythropoiesis; Erythropoietin; Humans; Recombinant Proteins; Vascular Diseases

Data from four prospective, multicenter, randomized studies involving 869 major, elective orthopedic surgery patients were examined by means of a retrospective integrated analysis to evaluate whether perioperative Epoetin alfa use was associated with the occurrence of thrombotic/vascular events. The incidence of thrombotic/vascular events was similar between 619 patients treated with Epoetin alfa and 250 patients receiving placebo (7.4% versus 8.0%, respectively). Regression analyses identified age, cardiac history, hypertension, and cardiac medications, but not Epoetin alfa, as risk factors for thrombotic/vascular events. The analysis did not implicate an increase in the rate of rise in hematocrit or maximum hematocrit obtained prior to surgery as contributors to thrombotic events. Thus, Epoetin alfa, which enhances preoperative erythropoiesis and increases hematocrit, did not affect the probability of thrombotic/vascular events.

Topics: Epoetin Alfa; Erythrocyte Count; Erythropoietin; Hematinics; Hematocrit; Hip; Humans; Incidence; Knee; Multicenter Studies as Topic; Placebos; Postoperative Complications; Prospective Studies; Randomized Controlled Trials as Topic; Recombinant Proteins; Regression Analysis; Retrospective Studies; Risk Factors; Thrombosis; Vascular Diseases

Numerous animal studies and clinical trials have demonstrated that erythropoietin (EPO) has therapeutic effects in ischemic and degenerative diseases. However, few clinical trials have investigated the effect of EPO in Parkinson's disease (PD) patients. This study was an exploratory pilot study to investigate the effects of recombinant human EPO (rhEPO) on motor and non-motor symptoms (NMS) in PD patients.. A total of 26 PD patients at the Hanyang University Hospital were enrolled in the study. The participants were randomly assigned to rhEPO and placebo groups. The rhEPO group was infused intravenously (40,000 IU each) twice a week for 5 weeks. Clinical improvement was estimated using the Unified Parkinson's Disease Rating Scale-III (UPDRS-III), the NMS Scale (NMSS) and the 39-Item Parkinson's Disease Questionnaire (PDQ-39). [(18)F] N-(3-fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane (FP-CIT) photon emission tomography (PET) scanning was performed on each participant at baseline and again after 12 months.. The rhEPO administration significantly improved the NMSS and PDQ-39 scores at 12 months. The UPDRS-III, which reflects motor function, did not change significantly after the rhEPO treatment. With the NMSS, the domains of cardiovascular autonomic function, sleep/fatigue, mood/cognition and attention/memory showed significant changes. None of the participants experienced any serious adverse effects.. We found that rhEPO had beneficial effects on NMS but not on motor function. Dopaminergic refractory NMS, such as cardiovascular autonomic dysfunction and cognition, showed improvement after the administration of rhEPO. Our results suggest that rhEPO might be a good candidate for the treatment of NMS in PD patients.

Topics: Aged; Aged, 80 and over; Brain; Cognition Disorders; Erythropoietin; Female; Humans; Male; Mental Disorders; Middle Aged; Parkinson Disease; Positron-Emission Tomography; Prospective Studies; Single-Blind Method; Sleep Wake Disorders; Surveys and Questionnaires; Time Factors; Tomography, X-Ray Computed; Tropanes; Vascular Diseases

Topics: Erythropoietin; Hemoglobins, Abnormal; Humans; Oxygen; Polycythemia; Vascular Diseases

An imbalance of proangiogenic and antiangiogenic factors is thought to induce the widespread vascular dysfunction characteristic of preeclampsia (PreE). Erythropoietin (Epo), a pleiotropic cytokine, has important angiogenic and vasoactive properties; however, its contribution to maternal vascular dysfunction in PreE is unknown.. Because high altitude (HA) raises the incidence of PreE, we asked whether HA increased maternal Epo and soluble Epo receptor (sEpoR) levels and whether such effects differed between PreE and normotensive controls at HA.. Longitudinal studies were conducted in pregnant Andean residents at HA (n = 28; 3600 m) or sea level (SL; n = 16; 300 m). Cross-sectional studies included 34 gestational age‒matched Andean PreE cases (n = 17) and controls (n = 17) in La Paz-El Alto, Bolivia (3600 to 4100 m).. HA augmented the pregnancy-associated rise in Epo relative to SL (P = 0.002), despite similar reductions in hemoglobin (Hb) across pregnancy at each altitude (7% to 9%, P < 0.001 for both). HA PreE cases had circulating Epo levels equivalent to those of controls but greater sEpoR (P < 0.05) and reduced Hb (P = 0.06, trend).. Our findings suggest that an augmented pregnancy-associated rise in Epo may be important for successful vascular adaptation to pregnancy at HA. We further speculate that the elevated sEpoR observed in PreE vs controls at HA impedes the effect of Epo to maintain endothelial function and may, in turn, be of pathological relevance for PreE at HA.

Topics: Adaptation, Physiological; Adult; Altitude; Biomarkers; Bolivia; California; Case-Control Studies; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Follow-Up Studies; Humans; Hypoxia; Incidence; Longitudinal Studies; Male; Pregnancy; Pregnancy Complications; Prognosis; Receptors, Erythropoietin; Vascular Diseases

Several polymorphisms of vasoactive hormones have been implicated in hypertension. Erythropoietin (EPO) interacts with vasoactive substances, such as angiotensin II. Previously detected single nucleotide polymorphisms in the hypoxia-responsive element of EPO might be associated with hypertension and hypertensive end organ damages.. 400 hypertensive patients and 200 age- and gender-matched normotensive controls were genotyped for an EPO polymorphism [cytosine (C)/thymine (T) single nucleotide polymorphism] at position 3434. Patients were grouped according to their genotype into the CC group (CC genotype) and the CT/TT group (CT and TT genotype). BP was measured by ambulatory BP monitoring.. The CC genotype was present in 87% of hypertensive patients and in 78.5% of controls (p = 0.007). In addition, patients with the CC genotype had higher BP levels compared with CT/TT genotypes (BPsys 143.7 ± 20.4 vs. 136.1 ± 13.5 mm Hg, p = 0.01, and BPdias 85.8 ± 11.6 vs. 82.4 ± 8.9, p = 0.043) despite a nearly identical number of antihypertensive drugs (2.3 ± 1.5 vs. 2.3 ± 1.6; p = 0.257). 100% of the small number of patients with end-stage renal disease (n = 15) had the CC genotype.. The CC genotype of the EPO gene at position 3434 is more frequently found in patients with hypertension and is associated with higher BP levels.

Topics: Adult; Aged; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Erythropoietin; Female; Genotype; Homozygote; Humans; Hypertension, Renal; Hypoxia; Male; Middle Aged; Myocardial Infarction; Polymorphism, Genetic; Stroke; Vascular Diseases

Erythropoietin (EPO) is a hypoxia-inducible hormone that is essential for normal erythropoiesis in the bone marrow. Administration of recombinant human-EPO is currently being used for the therapy of anemia associated with chronic renal failure and cancer. Moreover, EPO reduces organ injury in experimental hemorrhagic as well as in splanchnic artery occlusion shock and preserves cardiac function after experimental cardiac I/R. Erythropoietin receptors are widely distributed in the cardiovascular system, including endothelial, smooth muscle, cardiac, and other cell types, and nonhematopoietic effects of EPO are increasingly recognized. Thus, the vasculature may be a biological target of EPO. Therefore, the aim of our study was to investigate whether EPO exerts a protective effect in septic shock by modulating vascular dysfunction and hyporeactivity. Rats received EPO (300 U/kg, i.v.) or vehicle 30 min before and 1 and 3 h after LPS (8 x 10 U/kg, i.v.). In vivo and ex vivo (aortic rings) experiments were performed to evaluate the vascular response to contracting and vasodilating agents. The expression of iNOS, intercellular adhesion molecule 1, poly(ADP)ribose polymerase, Bcl-xl, and Bcl-2 was evaluated by Western blot analysis in the rat aorta. We demonstrate that EPO significantly prevents LPS-induced vascular hyporeactivity and endothelial dysfunction. Interestingly, EPO inhibits the increase in iNOS, poly(ADP)ribose polymerase, and intercellular adhesion molecule 1 expression in the aorta of endotoxemic rats and attenuated the decline in the expression of both Bcl-xl and Bcl-2 caused by LPS. In conclusion, our data support the view that EPO has important nonerythropoietic effects protecting organ and tissue against injury and indicate that EPO may be useful in the therapy of patients with septic shock.

Topics: Acetylcholine; Animals; bcl-X Protein; Blotting, Western; Endothelium, Vascular; Erythropoietin; Humans; Intercellular Adhesion Molecule-1; Lipopolysaccharides; Male; Nitric Oxide Synthase Type II; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar; Recombinant Proteins; Time Factors; Vascular Diseases; Vasoconstrictor Agents; Vasodilator Agents

Patients with advanced chronic renal disease (CRD) suffer from excessive morbidity and mortality due to complications of accelerated atherosclerosis. Recombinant human erythropoietin (EPO), which is routinely used to treat the anaemia present in approximately 90% of dialysis-dependent patients with end-stage renal disease, may induce vascular dysfunction by reducing nitric oxide (NO) availability. Pathophysiologic concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), are found in patients with CRD and correlate with vascular disease and cardiovascular mortality. The aim of the current study was to investigate the effect of EPO on ADMA concentrations and NO generation in vitro and in vivo. Furthermore, we wanted to study the effect of EPO on the expression of the enzymes that regulate ADMA metabolism and NO generation.. Human umbilical vein endothelial cells (HUVECs) were exposed to therapeutic concentrations of EPO. The expression and metabolic activity of dimethylarginine dimethylaminohydrolase II (DDAH II), the enzyme that degrades ADMA, was evaluated. Following subcutaneous administration of EPO to Balb/c mice for 10 weeks, serum ADMA concentrations were determined. Systolic blood pressure was measured noninvasively. Urinary nitrite and nitrate (NOx) concentrations were assessed by Griess assay. Protein expression of DDAH and NOS in livers and kidneys was measured by western blotting.. EPO suppressed ADMA elaboration by HUVECs. Systolic blood pressure and serum concentrations of ADMA were significantly elevated in EPO-treated mice. The protein expression of DDAH I in the kidney and liver was upregulated while hepatic expression of DDAH II was decreased and renal DDAH II expression remained unchanged by EPO administration. However, EPO augmented urinary NOx concentrations as well as the expression of NOS 1 and NOS 2 in the kidney.. In spite of elevating serum ADMA concentrations, EPO does not appear to compromise overall NO generation in Balb/c mice.

Topics: Amidohydrolases; Animals; Arginine; Base Sequence; Cells, Cultured; DNA Primers; Endothelial Cells; Epoetin Alfa; Erythropoietin; Humans; Kidney; Kidney Failure, Chronic; Liver; Male; Mice; Mice, Inbred BALB C; Nitric Oxide; Nitric Oxide Synthase Type II; Recombinant Proteins; Up-Regulation; Vascular Diseases

Diabetic retinopathy is a leading cause of visual disturbance in adults. In proliferative diabetic retinopathy, ischemia-induced pathologic growth of new blood vessels often causes catastrophic loss of vision. Besides VEGF, the existence of another potent ischemia-induced angiogenic factor is postulated. Since ischemia-inducible erythropoietin (Epo) has recently been identified its angiogenic properties, we investigated its potential role during retinal angiogenesis in proliferative diabetic retinopathy (PDR). The vitreous Epo level in patients with PDR was significantly higher than that in nondiabetic patients. Multivariate logistic regression analyses indicated that Epo and VEGF were independently associated with PDR and that Epo was more strongly associated with PDR than VEGF. Blockade of Epo inhibits retinal neovascularization in vivo, and inhibits endothelial cell proliferation response to PDR vitreous in vitro. Our data provide strong evidence that erythropoietin is a potent retinal angiogenic factor independent of VEGF and is capable of stimulating ischemia-induced retinal angiogenesis in proliferative diabetic retinopathy. Inhibition of such molecular mechanisms in the retinal angiogenesis could be a new therapeutical strategy in halting or preventing pathologic angiogenesis in diabetic retinopathy.

Topics: Diabetic Retinopathy; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Humans; Neovascularization, Pathologic; Retinal Vessels; RNA, Messenger; Vascular Diseases; Vascular Endothelial Growth Factor A

Repeated access to the circulation is essential to perform adequate maintenance hemodialysis (HD). Dysfunction of fistulae is the most common reason for a second intervention and recurrent hospitalization. The aim of this study was to evaluate the complications of HD fistulas seeking to evaluate the impact of age, site of arteriovenous fistula (AVF) (proximal or distal), side (left or right), and history of previous vascular access. We evaluated the clinical complications in 273 patients from the beginning of the use of the current access using the history and physical examination obtained at every dialysis session. We performed further investigations including doppler ultrasound or spiral computed tomography to confirm the clinical diagnosis. Of our patients, 40% had diabetes mellitus as the cause of end-stage renal disease. Almost half (49%) the patients dialyzed through an AVF and 13% with a catheter. One hundred eighty-four cases (67.6%) experienced complications. Of 145 cases that had elbow AVFs, 103 cases (71%) had complications; of 128 cases with wrist AVFs, 80 cases (62.5%) had complications. There were 115 (62.5%) complicated cases among 185 patients with left AVFs, and 69 (78%) among 88 patients with right AVFs. The rate of AVF complications increased with age. The 1-year survival rate was 94%. We did not observe any significant difference between AVF complications in patients with diabetes mellitus or hypertension as the underlying cause of renal failure. Mean cholesterol plasma level did not differ significantly between the patients with and without AVF complications. Mean hematocrit levels were not significantly different between the two groups. However, mean EPO weekly dose was significantly higher among the group of patients with AVF complications. We did find that rate of complications increased with age (P<.05). Our results showed that the frequency of complications was higher among patients with elbow and right-side AVFs, and also among patients with a history of a previous failed shunt but no significant relationship was observed between these variables (P>.05).

Topics: Adolescent; Adult; Arteriovenous Fistula; Erythropoietin; Functional Laterality; Hematocrit; Humans; Middle Aged; Renal Dialysis; Retrospective Studies; Risk Factors; Vascular Diseases

Sickle cell disease (SCD) results in chronic hypoxia and secondarily increased erythropoietin concentrations. Leukocytosis and activated monocytes are also observed in SCD in absence of infection or vaso-occlusion (steady state), the reasons for which are unknown. We found that erythroid cells produced placenta growth factor (PlGF), an angiogenic growth factor belonging to the vascular endothelial growth factor (VEGF) family, and its expression was induced in bone marrow CD34+ progenitor cells in the presence of erythropoietin. Furthermore, the steady state circulating PlGF levels in subjects with severe SCD (at least 3 vaso-occlusive crises [VOCs] per year) were 18.5 +/- 1.2 pg/mL (n = 9) compared with 15.5 +/- 1.2 pg/mL (n = 13) in those with mild SCD (fewer than 3 VOCs per year) and 11.3 +/- 0.7 pg/mL (n = 9) in healthy controls (P <.05), suggesting a correlation between PlGF levels and SCD severity. In addition, PlGF significantly increased mRNA levels of the proinflammatory cytochemokines interleukin-1beta, interleukin-8, monocyte chemoattractant protein-1, and VEGF in peripheral blood mononuclear cells (MNCs) of healthy subjects (n = 4; P <.05). Expression of these same cytochemokines was significantly increased in MNCs from subjects with SCD at steady state (n = 14), compared with healthy controls. Of the leukocyte subfractions, PlGF stimulated monocyte chemotaxis (P <.05, n = 3). Taken together, these data show for the first time that erythroid cells intrinsically release a factor that can directly activate monocytes to increase inflammation. The baseline inflammation seen in SCD has always been attributed to sequelae secondary to the sickling phenomenon. We show that PlGF contributes to the inflammation observed in SCD and increases the incidence of vaso-occlusive events.

Topics: Anemia, Sickle Cell; Antigens, CD34; Bone Marrow; Chemokines; Chemotaxis; Child; Child, Preschool; Cytokines; DNA; DNA-Binding Proteins; Erythroid Precursor Cells; Erythropoietin; Humans; Leukocytes; Monocytes; Placenta Growth Factor; Pregnancy Proteins; Severity of Illness Index; Statistics as Topic; Transcription Factor MTF-1; Transcription Factors; Vascular Diseases

Vascular calcifications are frequent in hemodialysis patients. Its incidence ranges from 25 to 67% depending of different series. Thirty hemodialysis patients were selected from a dialysis population of 150 patients. These 30 patients were divided into two groups: group I included 15 hemodialysis patients with severe secondary hyperparathyroidism and severe, roentgenographically visible diffuse vascular calcifications, and group II included 15 other hemodialysis patients with moderate hyperparathyroidism without radiographic evidence of arterial calcifications. The control group comprised 20 normal volunteers. In all patients, measurements of protein C activity, free protein S and intact parathyroid hormone (PTH) were performed. Statistical analysis showed that free protein S in the patients of group I had a tendency to be lower than in the patients of group II (p < 0.01) and the control group (p < 0.001). We did not find significant differences in free protein S between group II and control group patients nor a significant correlation between intact PTH and free protein S in groups I and II. Protein C activity was found to be in the normal range in both groups. Free protein S deficiency in patients of group I would suggest a synthesis defect by impaired endothelial cells-due to vascular calcifications (?). Free protein S deficiency could increase the risk of thrombotic complications in these patients.

Topics: Adult; Calcinosis; Erythropoietin; Female; Humans; Male; Middle Aged; Parathyroid Hormone; Protein C; Protein S; Protein S Deficiency; Recombinant Proteins; Reference Values; Renal Dialysis; Vascular Diseases

Topics: Blood Volume Determination; Cardiac Catheterization; Diagnosis, Differential; Erythropoietin; Fluoxymesterone; Hemodynamics; Humans; Male; Middle Aged; Polycythemia; Polycythemia Vera; Radionuclide Imaging; Respiratory Function Tests; Skin Diseases; Vascular Diseases

Erythropoiesis was evaluated in 37 patients with sickle cell anaemia, 26 of them children under 12 years of age. Mean haemoglobin, haematocrit, reticulocyte, and erythropoietin levels were similar for 11 who were asymptomatic, 11 with infections, and 12 in vaso-occlusive crisis. Mean haemoglobin, haematocrit, and reticulocyte values were significantly lower and the mean erythropoietin level significantly higher for three patients in aplastic crisis. Reticulocyte counts reflected erythropoietic activity during the asymptomatic state but were variable during infection and crisis. No erythropoietic inhibitory activity was found in any of the four clinical states. It has been suggested that erythropoietin production decreases during infection. Patients in this study responded appropriately to stress, showing no decrease in erythropoietic activity during acute infection or crisis.

Topics: Adolescent; Adult; Anemia, Sickle Cell; Blood Cell Count; Child; Child, Preschool; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Infant; Infections; Male; Reticulocytes; Thrombosis; Vascular Diseases

A case study is presented of a 55-year-old man who had clear cell renal carcinoma with pulmonary metastases and erythrocytosis. The increase in red blood cell mass was associated with an elevation in erythropoietic stimulatory activity in serum, pleural fluid, and tumor-cyst fluid as determined by the exhypoxic polycythemic mouse assay. It is postulated that the increased erythropoietic stimulatory activity represents autonomous tumor secretion of erythropoietin or an erythropoietin-like material. Electron microscopic studies confirmed the proximal tubular origin of this tumor.

Topics: Adenocarcinoma; Erythropoiesis; Erythropoietin; Humans; Hypoxia; Kidney Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Polycythemia; Renal Veins; Vascular Diseases