Role Of Urotensin II Research Articles

Urotensin II Enhances Advanced Aortic Atherosclerosis Formation and Delays Plaque Regression in Hyperlipidemic Rabbits.

Accumulated evidence shows that elevated urotensin II (UII) levels are associated with cardiovascular diseases. However, the role of UII in the initiation, progression, and regression of atherosclerosis remains to be verified. Different stages of atherosclerosis were induced in rabbits by a 0.3% high cholesterol diet (HCD) feeding, and either UII (5.4 μg/kg/h) or saline was chronically infused via osmotic mini-pumps. UII promoted atherosclerotic fatty streak formation in ovariectomized female rabbits (34% increase in gross lesion and 93% increase in microscopic lesion), and in male rabbits (39% increase in gross lesion). UII infusion significantly increased the plaque size of the carotid and subclavian arteries (69% increase over the control). In addition, UII infusion significantly enhanced the development of coronary lesions by increasing plaque size and lumen stenosis. Histopathological analysis revealed that aortic lesions in the UII group were characterized by increasing lesional macrophages, lipid deposition, and intra-plaque neovessel formation. UII infusion also significantly delayed the regression of atherosclerosis in rabbits by increasing the intra-plaque macrophage ratio. Furthermore, UII treatment led to a significant increase in NOX2 and HIF-1α/VEGF-A expression accompanied by increased reactive oxygen species levels in cultured macrophages. Tubule formation assays showed that UII exerted a pro-angiogenic effect in cultured endothelial cell lines and this effect was partly inhibited by urantide, a UII receptor antagonist. These findings suggest that UII can accelerate aortic and coronary plaque formation and enhance aortic plaque vulnerability, but delay the regression of atherosclerosis. The role of UII on angiogenesis in the lesion may be involved in complex plaque development.

The Role of Urotensin-II in Obesity and Metabolic Syndrome in Pediatric Population.

Background: Urotensin-II (U-II) is a short cyclic peptide that is widely recognized as one of the most potent vasoconstrictors. U-II plays a role in the pathophysiology of MS, participating in the development of essential hypertension, insulin resistance, hyperglycemia, and a proinflammatory state. Methods: This study comprised 52 obese children and adolescents with a body mass index (BMI) z score > 2, aged 10 to 18 years. Serum levels of U-II were assessed using an enzyme-linked immunosorbent assay along with other standard biochemical parameters. Results: Elevated serum levels of U-II were recorded in the group of obese subjects with MS when compared with the group of obese subjects without MS (4.99 (8.97–3.16) vs. 4.17 (5.17–2.03) ng/mL, median and IQR, p = 0.026). Furthermore, a subgroup of study subjects with high blood pressure had significantly higher U-II levels in comparison with the normotensive subgroup (4.98 (7.19–3.22) vs. 3.32 (5.06–1.97) ng/mL, p = 0.027), while the subgroup with a positive family history of high blood pressure had significantly higher U-II levels when compared with subjects who had a negative family history of elevated blood pressure (5.06 (6.83–4.45) vs. 3.32 (6.13–2.21) ng/mL, p = 0.039). Conclusions: To the best of the author’s knowledge, this is the first study on the levels of U-II in obese children and adolescents, including a possible link to MS.

Association between Plasma Urotensin II and Risk of Hypertension: Findings from a Prospective Study.

Up to date, human urotensin II (UII) is the most potent vasoconstrictor in mammalian animals. To explore whether UII played an important role in the development of hypertension, we conducted a prospective study in Changshu city, China. The baseline investigation was carried out in 2007, and the first follow-up investigation was conducted in 2013. From the participants, we randomly obtained 2000 normotensive subjects aged 40 years and older without any severe disease at baseline and examined plasma UII and endothelin-1 (ET-1) with their blood samples at baseline. Logistic models were used to analyze the association between baseline UII, baseline ET-1, and newly occurring hypertension. In 1,819 subjects with complete data, 723 subjects developed into hypertensive in about five years. After adjusting some potential confounders, the odds ratio (95% confidence interval) for risk of hypertension comparing the highest with the lowest quartile of baseline UII was 0.888 (0.689–1.144). The role of UII in the development of hypertension was not found in the current study; therefore, further research studies should be conducted to explore the relationship between UII and hypertension.

Role of Urotensin-II in Saphenous Vein Graft Disease.

ObjectiveTo elucidate the effect of diabetes mellitus (DM) on the atherosclerotic process in saphenous vein grafts by determining urotensin-II (U-II) levels in harvested saphenous veins of patients who underwent coronary artery bypass grafting (CABG).MethodsCoronary artery disease (CAD) patients who underwent CABG were divided into two groups: Group I (eight non-diabetic patients; CAD group) and Group II (13 patients; DM+CAD group). All patients underwent coronary angiography prior to surgery and Gensini score was used to determine the severity of coronary atherosclerosis. Saphenous vein samples were stained with hematoxylin-eosin and U-II, then damage score, H-Score, and vein layer thicknesses were calculated and statistically evaluated.ResultsIn light microscopic evaluation, significant difference was observed between the groups in terms of endothelial cells damage, internal elastic lamina degradation, and tunica media vascular smooth muscle cells (VSMCs) damage (P<0.001). U-II immunoreactivity was increased in tunica adventitia in the DM+CAD group (P=0.002). The increase in foam cells was directly proportional to the thickening of the subendothelial layer, and this increased U-II immunoreactivity. Gensini score was higher in the DM+CAD group than in the CAD group (P=0.002).ConclusionOur results show that saphenous vein grafts are already atherosclerotic before they are grafted in CAD patients. This disease is more severe in diabetic CAD patients and these changes can be detected using U-II immunoreactivity.

Plasma urotensin-2 level and Thr21Met but not Ser89Asn polymorphisms of the urotensin-2 gene are associated with migraines.

BackgroundUrotensin-II (U-II) is a peptide recognized by its potent vasoconstrictor activity in many vascular events, however the role of urotensin-II in migraine has not been considered yet. The molecular mechanisms and genetics of migraine have not been fully clarified yet, but it is well-known that vascular changes considerably contribute in pathophysiology of migraine and also its complications. The aim of this study was to analyze the plasma U-II levels along with genotype distributions and allele frequencies for UTS2 Thr21Met and Ser89Asn polymorphisms among the patients with migraine without aura (MWoA).MethodsOne hundred eighty-six patients with MWoA and 171 healthy individuals were included in this study. Plasma U-II levels were measured in attack free period. The genotype and allele frequencies for the Thr21Met (T21M) and Ser89Asn (S89N) polymorphisms in the UTS2 gene were analyzed.ResultsPlasma U-II levels were significantly higher in MWoA patients (p = 0.002). We detected a significant association between the T21M polymorphism in the UTS2 gene and migraine (53.8 % in patients, 40.4 % in controls, p = 0.035), but not with S89N polymorphism (p = 0.620). A significant relationship was found between U-II levels and MIDAS score (β = 0.508, p = 0.001).ConclusionOur study suggests that U-II may play a role in migraine pathogenesis; also Thr21Met polymorphism was associated with the risk of migraine disease. Further studies are needed for considering the role of U-II in migraine pathophysiology and for deciding if UTS2 gene may be a novel candidate gene in migraine cases.

The role of the UTS2 gene polymorphisms and plasma Urotensin-II levels in breast cancer.

Breast cancer is the most common malignancy predominantly affecting women. To date, numerous numbers of studies were reported novel genetic contributors with diagnostic, prognostic, and therapeutic potential for the breast carcinogenesis. However, the role of urotensin-II in breast carcinogenesis has not been elucidated yet. Urotensin-II is a somatostatin-like cyclic tiny peptide identified by its potent vasoconstrictor activity. Soon after its discovery, its involvement in many disease states as well as its expression in various tissues including the tumors have been demonstrated. Moreover, there is strong evidence that suggest urotensin-II as the significant contributor of angiogenesis as well as cell proliferation and tumor biology. In this study, enzyme-linked immunosorbent assay (ELISA) and restriction fragment length polymorphism analysis were used to evaluate plasma levels of urotensin-II and Thr21Met and Ser89Asn polymorphisms of UTS2 gene in breast cancer patients. In the present case-control study, we noticed a significant decrease in the levels of urotensin-II protein in the plasma of the breast cancer patients (p < 0.05). Also, Thr21Met polymorphism in the UTS2 gene was associated with the risk of developing breast cancer (p < 0.0001), whereas the genotype frequency of Ser89Asn was found to be similar in patients and controls (p > 0.05). In addition, we demonstrated the gradual decreasing of urotensin-II protein levels from TT and TM to MM genotypes. In conclusion, these results strongly suggest that urotensin-II could contribute to breast carcinogenesis and Thr21Met polymorphism can be an important risk factor in developing breast tumors.

Urotensin II promotes the proliferation of endothelial progenitor cells through p38 and p44/42 MAPK activation

Urotensin II (UII) is a vasoactive peptide with many potent effects in the cardiorenovascular system and is also possibly involved in the pathogenesis of atherosclerosis. Endothelial progenitor cells (EPCs) are involved in angiogenesis and vascular homeostasis and may be important in the maintenance of endothelial integrity. The aim of this study was to investigate whether UII has an effect on the proliferation of bone marrow-derived EPCs and the possible signaling mechanisms involved. Bone marrow-derived EPCs were isolated from male Sprague-Dawley rats and cultured in medium containing 5% fetal bovine serum. Cells were incubated with UII for 24 h. The proliferation of EPCs was analyzed by MTT assay. Western blotting was performed to determine the phosphorylation levels of mitogen-activated protein kinases (MAPKs). The results demonstrated that UII promoted the proliferation of EPCs in a concentration-dependent manner in a certain range, and the proliferation was largely suppressed by inhibitors of GPR14 and MAPKs (p38 and p44/42). UII significantly increased the phosphorylation levels of p38MAPK and p44/42MAPK, and these effects were significantly inhibited by respective inhibitors. These findings indicate that UII promotes the proliferation of rat bone marrow-derived EPCs through a process that involves MAPK activation, and provides novel insights regarding the role of UII in the EPC-mediated repair of atherosclerotic injury.

Role of urotensin-II in the pathogenesis of liver cirrhosis and portal hypertension and collateral circulation

Role of urotensin-II in the pathogenesis of liver cirrhosis and portal hypertension and collateral circulation

Urotensin II Immunoreactivity in the Human Circulation: Evidence for Widespread Tissue Release

The sources of secretion and clearance of plasma urotensin II (UII) in the human circulation remain uncertain and may be relevant to understanding the role of UII in human physiology and cardiovascular disease. In 94 subjects undergoing clinically indicated cardiac catheterization, we collected blood samples from arterial and multiple venous sites to measure transorgan gradients of plasma UII immunoreactivity. Net UII release occurred (in descending order of proportional transorgan gradient) across the heart, kidney, head and neck, liver, lower limb, and pulmonary circulations (P < 0.01). Although no specific clearance site was localized, the absence of an overall subdiaphragmatic aorto-caval peptide gradient indicated that there were lower body segment sites of UII clearance as well as secretion. The proportional increase in UII immunoreactivity was significantly correlated across all sites of net peptide release within an individual (P < or = 0.05). In univariate analyses, mixed venous UII concentrations were correlated with diagnosis of acute coronary syndrome and femoral artery oxygen tension and inversely with systolic blood pressure and body mass index. Diagnosis of acute coronary syndrome and body mass index were independent predictors of mixed venous UII immunoreactivity in multivariate analysis. No correlates of net cardiac UII release were identified. UII is secreted from the heart and multiple other tissues into the circulation. Related increments in UII immunoreactivity across multiple tissue sites suggest that peptide release occurs via a shared mechanism. Increased UII immunoreactivity is observed in subjects with acute coronary syndrome.

Urotensin II Induces Migration of Endothelial Progenitor Cells via Activation of the RhoA/Rho Kinase Pathway

Urotensin II (UII) is a vasoactive peptide with many potent effects in the cardiorenovascular system and may be involved in the pathogenesis of atherosclerosis. Cardiovascular risk factors are often accompanied by reduced numbers of endothelial progenitor cells (EPCs) and their impaired migratory capacity. However, the role of UII in the migration of EPCs has not been reported so far. The aim of this study was to investigate whether UII influences the chemotactic function of bone marrow-derived EPCs and the possible signaling mechanisms involved. As a ligand for the orphan G-protein coupled receptor 14 (GPR14, UT receptor), UII exerts vasoactive functions through activation of the RhoA/Rho kinase pathway. We therefore analyzed the expression of GPR14 mRNA and protein, the activation of RhoA kinase and the phosphorylation of myosin light chain (MLC) in EPCs, isolated from the rat bone marrow. EPCs of 1-4 passages expressed GPR14 mRNA and protein. Chemotaxis assays were performed using Transwell cell-culture chambers with UII (10(-10)-10(-6) M), showing that UII induced chemotaxis of EPCs in a concentration-dependent manner after 3-h treatment (all p < 0.05), with the highest value (about 3-fold increase) at 10(-8) M. UII caused rapid activation of RhoA and increased phosphorylation of MLC. Conversely, a Rho-kinase inhibitor Y-27632 prevented the UII-induced migration and the phosphorylation of MLC. In conclusion, GPR14/UT receptor is expressed in EPCs, and UII induces migration of EPCs via activation of the RhoA/Rho kinase pathway. These findings provide new insights into the actions of UII in atherosclerosis.

Abstract 2945: Normalization of Beta Adrenergic Receptor Signaling Improves Left Ventricular Myocyte Function with Urotensin II Receptor Blockade in Murine Heart Failure

Background. Urotensin II (UII), the most potent vasoconstrictor and its receptors (UT) are upregulated in heart failure (HF). Although the role of UII in cardiac regulation is not fully understood, increasing evidence suggests that in the failing myocardium, UII may exert an enhanced negative modulation on cardiac contractile performance and cardiac β-AR regulation, thus providing a potential mechanism for progressive deterioration in cardiac function in HF. We assessed the hypothesis that blocking UII may prevent HF-induced alterations in cardiac β-adrenergic receptor (AR) expression, restore normal β-adrenergic regulation, and improve left ventricular (LV) myocyte functional performance. Methods. We compared β 1 - and β 3 -AR expression and responses to β- and β 3 -AR stimulation in freshly isolated LV myocytes obtained from 3 groups of mice (6/group): 1) HF-2 months after receiving isoproterenol (ISO, 170 mg/kg, sq, for 2 days); 2) HF/UIIBK-one month after receiving ISO, then urantide, a potent UIIBK (10 −5 M/kg/day via sq implanted osmotic minipump) initiated after the onset of HF and given for 1 month; and 3) Controls. Results. Compared with controls, ISO-treated mice had established HF. Isolated cardiomyocyte studies showed about 42% reductions in cell contraction (dL/dt max , 78 vs 134 μm/s) and relaxation (dR/dt max , 69 vs 120 μm/s) with a much less increase in dL/dt max (29 vs 68%) and dR/dt max (31 vs 62%) in response to superfusion of ISO (10 −8 M). These changes were associated with significantly decreased β 1 -AR mRNA (40%, 0.57 vs 0.95), but increased β 3 -AR mRNA (54%, 0.43 vs 0.28) expression. Treatment with UII BK prevented HF-induced contrast changes of β 1 - and β 3 -AR mRNA expression. The signal ratios of β 1 -AR mRNA (0.85) and β 3 -AR mRNA (0.34) remained close to control levels. Basal and ISO-stimulated adenylate cyclase activity were normal, and ISO-induced increase in dL/dt max (61%) and dR/dt max (58%) were significantly augmented. Conclusion. In a murine model of progressive HF, chronic UIIBK prevents HF-induced contrast alterations of LV β 1 - and β 3 -AR expression, restores normal responsiveness of myocyte to β-AR stimulation, and improves LV myocyte function. Thus, UIIBK may provide a new therapeutic strategy for the treatment of HF.

Urotensin II in chronic liver disease: In vivo effect on vascular tone

Objective. Urotensin II (UII) is now recognized as the most potent human vasoconstrictor. Although its role in human pathophysiology is unknown, vasoactive mediators are known to be important in the pathogenesis of portal hypertension complicating chronic liver disease. The objective of this study was to investigate the role of UII in liver cirrhosis via examination of the in vivo effect of UII in this patient group. Material and methods. The vasoactive effects of UII were measured using Laser Doppler velocimetry on cirrhotic patients (n=14) and age-matched healthy controls (n=14) after UII administration by iontophoresis to the cutaneous microcirculation of the forearm. Results. In vivo administration of UII produced vasoconstriction of the cutaneous microcirculation in the cirrhotic group and vasodilatation in the controls, with values differing significantly at the two highest doses of UII: 10−9 mol (p=0.01) and 10−7 mol (p=0.004). Conclusions. UII mediates vasoconstriction of the microcirculation of cirrhotics but not of controls. This suggests that UII has pathophysiological relevance in the portal hypertensive population through its vasoactive properties. Further studies of UII and UII-antagonists are warranted in this patient population.

Immunolocalization of urotensin II and its receptor in human adrenal tumors and attached non-neoplastic adrenal tissues

Urotensin II (UII), first identified from goby urophysis, is a potent vasoactive peptide hormone and an endogenous ligand for an orphan G protein-coupled receptor GPR14, now named urotensin II receptor (UT-R). In addition to its vascular actions, UII has been shown to have mitogenic effects on tumor growth and some regulatory effects on adrenal steroidogenesis. In the present study, we examined expression of UII and UT-R in human adrenal tumors and attached non-neoplastic adrenal tissues by immunohistochemistry. Both UII and UT-R were immunolocalized in tumor cells of all adrenal tumors examined: 8 cases of cortisol-producing adenomas, 8 cases of aldosterone-producing adenomas, 2 cases of non-functioning adenomas, 17 cases of adrenocortical carcinomas, and 8 cases of pheochromocytomas. In attached adrenals, immunoreactivity for UII was detected in medulla, but much weaker in the cortex than in cortical tumors, suggesting that expression of UII was up-regulated in neoplastic adrenocortical tissues. No significant differences were found in the degree of immunoreactivity for UT-R between the tumors and the attached adrenal tissues. The present study showed that both UII and UT-R were expressed in the adrenal tumors and attached non-neoplastic adrenal tissues, and suggests possible roles of UII and UT-R in tumor growth and/or secretory activities of these tumors.

Does cigarette smoking increase plasma urotensin II concentrations?

Human urotensin II (UII) acts on the urotensin (UT) receptor and is the most potent mammalian vasoconstrictor identified to date. The role of UII in human cardiovascular regulation remains unclear, and the results of plasma measurements have been conflicting, perhaps because different measurement techniques have been used. The effects of cigarette smoking on plasma UII concentrations are unknown. The primary aim of our study was to demonstrate whether cigarette smoking had any effect on plasma UII concentrations in otherwise healthy volunteers. Our secondary aim was to compare the results obtained from assaying simultaneously using both radioimmunoassay (RIA) and immunoluminometric assay (ILMA). Blood was taken from 20 healthy male non-smokers and 20 healthy male cigarette smokers. Plasma was separated and stored at -70 degrees C. Samples were batch analysed simultaneously for UII using RIA and ILMA. Median (range) plasma UII concentrations were lower in non-smokers [1.67 (1.0-2.27) pg ml(-1)] compared to smokers [2.62 (1.87-3.46) pg ml(-1)] (P = 0.03) measured using RIA. Those who had smoked a cigarette in the 10 min before sampling had greater concentrations of UII [3.10 (1.87-4.60) pg ml(-1)] compared to controls (P = 0.01). Plasma UII concentrations determined by ILMA were consistently low with no differences between groups. The data obtained by RIA show that smoking may increase plasma concentrations of UII with a more pronounced increase when a cigarette has been smoked recently. There was a complete lack of correlation between RIA and ILMA for the whole data set, which suggests that some of the variability in plasma UII reported in the literature may result from differences between assays.