No abstract available.
Endothelins ; Endothelium ; Hypertension ; Reactive Oxygen Species

BACKGROUND AND OBJECTIVES: Elevated endothelin (ET)-1 level is strongly correlated with the pathogenesis of pulmonary arterial hypertension (PAH). Expression level of nicotinamide adenine dinucleotide phosphate oxidase (NOX) 4 is increased in the PAH patients. Ambrisentan, a selective endothelin receptor A (ERA) antagonist, is widely used in PAH therapy. The current study was undertaken to evaluate the effects of ambrisentan treatment in the monocrotaline (MCT)-induced PAH rat model. METHODS: Rats were categorized into control group (C), monocrotaline group (M) and ambrisentan group (Am). The M and Am were subcutaneously injected 60 mg/kg MCT at day 0, and in Am, ambrisentan was orally administered the day after MCT injection for 4 weeks. The right ventricle (RV) pressure was measured and pathological changes of the lung tissues were observed by Victoria blue staining. Protein expressions of ET-1, ERA, endothelial nitric oxide synthase (eNOS) and NOX4 were confirmed by western blot analysis. RESULTS: Ambrisentan treatment resulted in a recovery of the body weight and RV/left ventricle+septum at week 4. The RV pressure was lowered at weeks 2 and 4 after ambrisentan administration. Medial wall thickening of pulmonary arterioles and the number of intra-acinar arteries were also attenuated by ambrisentan at week 4. Protein expression levels of ET-1 and eNOS were recovered at weeks 2 and 4, and ERA levels recovered at week 4. CONCLUSIONS: Ambrisentan administration resulted in the recovery of ET-1, ERA and eNOS protein expression levels in the PAH model. However, the expression level of NOX4 remained unaffected after ambrisentan treatment.
Animals ; Arteries ; Arterioles ; Blotting, Western ; Body Weight ; Endothelin Receptor Antagonists ; Endothelins ; Gene Expression ; Heart Ventricles ; Humans ; Hypertension ; Hypertension, Pulmonary ; Lung ; Models, Animal ; Monocrotaline ; NADP ; NADPH Oxidase ; Nitric Oxide Synthase Type III ; Oxidoreductases ; Rats ; Receptors, Endothelin ; Victoria

PURPOSE: Abnormal potassium channels expression affects vessel function, including vascular tone and proliferation rate. Diverse potassium channels, including voltage-gated potassium (Kv) channels, are involved in pathological changes of pulmonary arterial hypertension (PAH). Since the role of the Kv1.7 channel in PAH has not been previously studied, we investigated whether Kv1.7 channel expression changes in the lung tissue of a monocrotaline (MCT)-induced PAH rat model and whether this change is influenced by the endothelin (ET)-1 and reactive oxygen species (ROS) pathways. METHODS: Rats were separated into 2 groups: the control (C) group and the MCT (M) group (60 mg/kg MCT). A hemodynamic study was performed by catheterization into the external jugular vein to estimate the right ventricular pressure (RVP), and pathological changes in the lung tissue were investigated. Changes in protein and mRNA levels were confirmed by western blot and polymerase chain reaction analysis, respectively. RESULTS: MCT caused increased RVP, medial wall thickening of the pulmonary arterioles, and increased expression level of ET-1, ET receptor A, and NADPH oxidase (NOX) 4 proteins. Decreased Kv1.7 channel expression was detected in the lung tissue. Inward-rectifier channel 6.1 expression in the lung tissue also increased. We confirmed that ET-1 increased NOX4 level and decreased glutathione peroxidase-1 level in pulmonary artery smooth muscle cells (PASMCs). ET-1 increased ROS level in PASMCs. CONCLUSION: Decreased Kv1.7 channel expression might be caused by the ET-1 and ROS pathways and contributes to MCT-induced PAH.
Animals ; Arterioles ; Blotting, Western ; Catheterization ; Catheters ; Endothelins ; Glutathione ; Hemodynamics ; Hypertension* ; Jugular Veins ; Lung ; Models, Animal* ; Monocrotaline ; Myocytes, Smooth Muscle ; NADPH Oxidase ; Polymerase Chain Reaction ; Potassium ; Potassium Channels ; Potassium Channels, Voltage-Gated* ; Pulmonary Artery ; Rats* ; Reactive Oxygen Species ; RNA, Messenger ; Ventricular Pressure

BACKGROUND AND OBJECTIVES: Previous studies have shown that integrins alpha5beta1 (ITGA5B1) gene-modified rat bone marrow mesenchymal stem cells (rBMSCs) could prevent cell anoikis and increase the nitric oxide (NO) production. Here we examined the capability of rBMSCs/ITGA5B1 on the phenotype modulation of Human Pulmonary Artery Smooth Muscle Cell (HPASMC) in vitro. METHODS AND RESULTS: The synthetic (dedifferentiated) phenotype of HPASMC was induced by monocrotaline (MCT, 1μM) for 24 h and then co-cultured with rBMSCs/ITGA5B1 in a transwell culture system. The activation of NO/cGMP (nitric oxide/Guanosine-3′, 5′-cyclic monophosphate) signaling was investigated in HPASMC. The changes of pro-inflammatory factors, oxidative stress, vasodilator, vasoconstrictor, contractile and synthetic genes, and the morphological changes of HPASMC were investigated. The results of this study showed that the NO/cGMP signal, endothelial nitric oxide synthase (eNOS) expression, the expression of the vasoprotective genes heme oxygenase-1 (HMOX1) and prostaglandin-endoperoxide synthase 2 (PTGS2) were increased, but the expression of transforming growth factor-β1 (TGF-β1), CCAAT/enhancer-binding proteins delta (Cebpd), Krüppel-like factor 4 (KLF4), and activating transcription factor 4 (ATF4) were reduced in MCT treated HPASMC co-cultured with rBMSCs/ITGA5B1. The synthetic smooth muscle cells (SMCs) phenotype markers thrombospondin-1, epiregulin and the vasoconstrictor endothelin (ET)-1, thromboxane A2 receptor (TbxA2R) were down-regulated, whereas the contractile SMCs phenotype marker transgelin expression was up-regulated by rBMSCs/ITGA5B1. Furthermore, rBMSCs/ITGA5B1 promoted the morphological restoration from synthetic (dedifferentiation) to contractile (differentiation) phenotype in MCT treated HPASMC. CONCLUSIONS: rBMSCs/ITGA5B1 could inhibit inflammation and oxidative stress related genes to promote the HPASMC cell differentiation by activation NO/cGMP signal.
Activating Transcription Factor 4 ; Animals ; Anoikis ; Bone Marrow ; Cell Differentiation ; Endothelins ; Epiregulin ; Genes, Synthetic ; Heme Oxygenase-1 ; Humans ; In Vitro Techniques ; Inflammation ; Integrins ; Mesenchymal Stromal Cells ; Monocrotaline ; Muscle, Smooth, Vascular ; Myocytes, Smooth Muscle ; Nitric Oxide Synthase Type III ; Nitric Oxide ; Oxidative Stress ; Phenotype ; Prostaglandin-Endoperoxide Synthases ; Pulmonary Artery ; Rats ; Receptors, Thromboxane A2, Prostaglandin H2

Bone metastases are the main driver of morbidity and mortality in advanced prostate cancer. Targeting the bone microenvironment, a key player in the pathogenesis of bone metastasis, has become one of the mainstays of therapy in men with advanced prostate cancer. This review will evaluate the data supporting the use of bone-targeted therapy, including (1) bisphosphonates such as zoledronic acid, which directly target osteoclasts, (2) denosumab, a receptor activator of nuclear factor-kappa B (RANK) ligand inhibitor, which targets a key component of bone stromal interaction, and (3) radium-223, an alpha-emitting calcium mimetic, which hones to the metabolically active areas of osteoblastic metastasis and induces double-strand breaks in the DNA. Denosumab has shown enhanced delay in skeletal-related events compared to zoledronic acid in patients with metastatic castration-resistant prostate cancer (mCRPC). Data are mixed with regard to pain control as a primary measure of efficacy. New data call into question dosing frequency, with quarterly dosing strategy potentially achieving similar effect compared to monthly dosing for zoledronic acid. In the case of radium-223, there are data for both pain palliation and improved overall survival in mCRPC. Further studies are needed to optimize timing and combination strategies for bone-targeted therapies. Ongoing studies will explore the impact of combining bone-targeted therapy with investigational therapeutic agents such as immunotherapy, for advanced prostate cancer. Future studies should strive to develop biomarkers of response, in order to improve efficacy and cost-effectiveness of these agents.
Bone Density Conservation Agents/therapeutic use* ; Bone Neoplasms/secondary* ; Denosumab/therapeutic use* ; Diphosphonates/therapeutic use* ; Endothelins/antagonists & inhibitors* ; Humans ; Male ; Prostatic Neoplasms/pathology* ; Protein Kinase Inhibitors/therapeutic use* ; Radioisotopes/therapeutic use* ; Radiopharmaceuticals/therapeutic use* ; Radium/therapeutic use* ; Samarium/therapeutic use* ; Strontium Radioisotopes/therapeutic use*

OBJECTIVETo assess the association of single nucleotide polymorphisms (SNPs) of endotheline receptor gene with the severity of coronary heart disease (CHD).

METHODSA total of 553 CHD patients, including 324 patients with mult-vessel disease based on result of selected coronary angiography, and 553 age- and sex-frequency matched controls were selected. Clinical data were collected. Genotypes of rs501120, rs899997, rs1878406 and rs7173743 were determined with TaqMan-MGB probes.

RESULTSThe distribution of genotypes of the 4 SNPs showed no significant difference between the two groups. However, the frequency of A allele of rs501120 and T allele of rs1878406 were significantly higher in the CHD group compared with the control group (P< 0.05). For rs7173743 and rs899997, no significant difference was detected between the two groups. After adjusting for conventional risk factors by logistic regression analysis, the results suggested that the distribution of rs1878406 TT+TC genotype in severe multi-vessel disease group is significantly higher than that in the control group (OR=1.43, 95% CI: 1.05-2.07, P=0.033).

CONCLUSIONThe above results suggested that the rs1878406 polymorphism of endotheline receptor gene may serve as a genetic marker for severe multi-vessel disease in CHD among ethnic Han Chinese.

Case-Control Studies ; Coronary Disease ; genetics ; Endothelins ; genetics ; Female ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Multiple Chronic Conditions ; Polymorphism, Single Nucleotide ; genetics

Waardenburg syndrome (WS) is a rare genetic disorder, including clinical features of pigmentary abnormalities of irides, skin, hair and sensorineural hearing loss and facial dysmorphism. Among the four types, WS type IV (Waardenburg-Shah syndrome) additionally represents Hirschsprung's disease. Mutations in the SOX10, END3, or EDNRB genes are known to cause WS type IV. Here, we report a 6 year-old girl who was diagnosed as WS type IV by typical clinical manifestations, including skin hypopigmentation, heterochromia of both irides, unilateral sensorineural hearing loss, mild developmental delay and Hirschsprung's disease. The diagnosis was confirmed by molecular genetic analysis of EDNRB. Two novel EDNRB mutations were identified, and each mutation was segregated from each of her parents. During the follow-up period, the patient underwent a surgery for spleen torsion and was medically managed due to recurrent enterocolitis. Also, she suffered from impaired immunity including Hirschsprung's associated enterocolitis.
Diagnosis ; Endothelins* ; Enterocolitis ; Female ; Follow-Up Studies ; Hair ; Hearing Loss, Sensorineural ; Hirschsprung Disease ; Humans ; Hypopigmentation ; Molecular Biology ; Parents ; Receptor, Endothelin B ; Receptors, Endothelin* ; Skin ; Spleen ; Waardenburg Syndrome

BACKGROUND/AIMS: Irritable bowel syndrome (IBS) is a multifactorial disorder, involving dysregulation of brain-gut axis. Our aim was to evaluate the neuroendocrine activity in IBS. METHODS: Thirty IBS and 30 healthy volunteers were enrolled. Psychological symptoms were evaluated by questionnaires. Urinary 5-hydroxyindoleacetic acid, plasma serotonin (5-hydroxytryptamine, 5-HT), endothelin, and neuropeptide Y (NPY), and plasma and urinary cortisol levels were evaluated. Fourteen IBS subjects underwent microneurography to obtain multiunit recordings of efferent postganglionic muscle sympathetic nerve activity (MSNA). RESULTS: Prevalent psychological symptoms in IBS were maladjustment (60%), trait (40%) and state (17%) anxiety, obsessive compulsive-disorders (23%), and depressive symptoms (23%). IBS showed increased NPY (31.9 [43.7] vs 14.8 [18.1] pmol/L, P = 0.006), 5-HT (214.9 [182.6] vs 141.0 [45.5] pg/mL, P = 0.010), and endothelin [1.1 [1.4] vs 2.1 [8.1] pg/mL, P = 0.054], compared to healthy volunteers. Moreover, plasma NPY, endothelin, cortisol and 5-HT, and urinary 5-hydroxyindoleacetic acid were associated with some psychological disorders (P ≤ 0.05). Despite a similar resting MSNA, after cold pressor test, IBS showed a blunted increase in MSNA burst frequency (+4.1 vs +7.8 bursts/min, P = 0.048; +30.1% vs +78.1%, P = 0.023). Baseline MSNA tended to be associated with urinary cortisol (ρ = 0.557, P = 0.059). Moreover, changes in heart rate after mental stress were associated with urinary cortisol (ρ = 0.682, P = 0.021) and changes in MSNA after mental stress were associated with plasma cortisol (ρ = 0.671, P = 0.024).” CONCLUSION: Higher concentrations of endothelin, NPY, and 5-HT were found to be associated with some psychological disorders in IBS patients together with an altered cardiovascular autonomic reactivity to acute stressors compared to healthy volunteers.
Anxiety ; Autonomic Nervous System ; Depression ; Endothelin-1 ; Endothelins ; Healthy Volunteers ; Heart Rate ; Humans ; Hydrocortisone ; Irritable Bowel Syndrome* ; Neuropeptide Y ; Pilot Projects* ; Plasma ; Serotonin

OBJECTIVETo observe the effects of Danhong Injection (丹红注射液) and its main components, including daiclzein and hydroxysafflor yellow A (HSYA), on the anticoagulation, fibrinolysis, anti-apoptosis in hypoxia model of vein endothelial cells (VECs).

METHODSVECs were prepared and were put in a hypoxia environment, which consisted of mixed gas of 95% N and 5% CO mixed gas, when reached confluent culture. Five groups used different treatments, including normal control group, hypoxia group, daiclzein group, HSYA group and Danhong Injection group. The VECs were identified by fluorescence double labeling methods. The morphology was observed by a phase contrast microscopy. The effects of Danhong Injection, daiclzein and HSYA on 6 keto prostaglandin F1α (6-keto-PGF1α) level was measured by the method of radioimmunoassay (RIA). Superoxide dismutase (SOD) activity was tested by water soluble tetrazolium salt. The content of malondialdehyde (MDA) was measured by thiobarbituric acid. The activities of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) were measured by the method of chromogenic substrate. The contents of endothelin (ET) and nitric oxide (NO) were detected by non-equilibrium RIA and enzymelinked immunosorbent assay. Cells apoptosis rate was determined by flow cytometry.

RESULTSCompared with the normal control group, the floating cells number, PAI activity, ET and MDA contents, and cells apoptosis rate in the culture solution of hypoxia group were all significantly increased, whereas the 6-keto-PGF1α and NO contents, and t-PA and SOD activities were decreased significantly (P<0.01). Compared with the hypoxia group, Danhong Injection markedly increased the 6-keto-PGF1α content and SOD activity, regulated PAI and t-PA activities, ET and NO contents, and decreased MDA content and cells apoptosis rate (P<0.05 or P<0.01).

CONCLUSIONSDanhong Injection and its main components played an important role in protecting primary VECs from hypoxic damage by regulating the secretion and vasomotor function of VECs. The function of Danhong Injection was most remarkable.

6-Ketoprostaglandin F1 alpha ; metabolism ; Animals ; Apoptosis ; drug effects ; Blood Coagulation ; drug effects ; Cell Count ; Cells, Cultured ; Drugs, Chinese Herbal ; pharmacology ; Endothelial Cells ; drug effects ; metabolism ; Endothelins ; metabolism ; Factor VIII ; metabolism ; Fibrinolysis ; drug effects ; Fluorescent Antibody Technique ; Humans ; Infant, Newborn ; Injections ; Malondialdehyde ; metabolism ; Nitric Oxide ; metabolism ; Plasminogen Inactivators ; metabolism ; Rabbits ; Superoxide Dismutase ; metabolism ; Tissue Plasminogen Activator ; metabolism ; Umbilical Veins ; cytology

PURPOSE: Pulmonary arterial hypertension (PAH) leads to right ventricular failure (RVF) as well as an increase in pulmonary vascular resistance. Our purpose was to study the effect of sildenafil on right ventricular remodeling in a rat model of monocrotaline (MCT)-induced RVF. METHODS: The rats were distributed randomly into 3 groups. The control (C) group, the monocrotaline (M) group (MCT 60 mg/kg) and the sildenafil (S) group (MCT 60 mg/kg+ sildenafil 30 mg/kg/day for 28 days). Masson Trichrome staining was used for heart tissues. Western blot analysis and immunohistochemical staining were performed. RESULTS: The mean right ventricular pressure (RVP) was significantly lower in the S group at weeks 1, 2, and 4. The number of intra-acinar arteries and the medial wall thickness of the pulmonary arterioles significantly lessened in the S group at week 4. The collagen content also decreased in heart tissues in the S group at week 4. Protein expression levels of B-cell lymphoma-2 (Bcl-2)-associated X, caspase-3, Bcl-2, interleukin (IL)-6, matrix metalloproteinase (MMP)-2, endothelial nitric oxide synthase (eNOS), endothelin (ET)-1 and ET receptor A (ERA) in lung tissues greatly decreased in the S group at week 4 according to immunohistochemical staining. According to Western blotting, protein expression levels of troponin I, brain natriuretic peptide, caspase-3, Bcl-2, tumor necrosis factor-α, IL-6, MMP-2, eNOS, ET-1, and ERA in heart tissues greatly diminished in the S group at week 4. CONCLUSION: Sildenafil alleviated right ventricular hypertrophy and mean RVP. These data suggest that sildenafil improves right ventricular function.
Animals ; Arteries ; Arterioles ; B-Lymphocytes ; Blotting, Western ; Caspase 3 ; Collagen ; Endothelins ; Gene Expression ; Heart ; Hypertension ; Hypertension, Pulmonary ; Hypertrophy, Right Ventricular ; Interleukin-6 ; Interleukins ; Lung ; Models, Animal* ; Monocrotaline ; Natriuretic Peptide, Brain ; Necrosis ; Nitric Oxide Synthase Type III ; Rats* ; Sildenafil Citrate* ; Troponin I ; Vascular Resistance ; Ventricular Function, Right ; Ventricular Pressure ; Ventricular Remodeling*