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1.  Urotensin II Protects Cardiomyocytes from Apoptosis Induced by Oxidative Stress through the CSE/H2S Pathway 
Plasma urotensin II (UII) has been observed to be raised in patients with acute myocardial infarction; suggesting a possible cardiac protective role for this peptide. However, the molecular mechanism is unclear. Here, we treated cultured cardiomyocytes with H2O2 to induce oxidative stress; observed the effect of UII on H2O2-induced apoptosis and explored potential mechanisms. UII pretreatment significantly reduced the number of apoptotic cardiomyocytes induced by H2O2; and it partly abolished the increase of pro-apoptotic protein Bax and the decrease of anti-apoptotic protein Bcl-2 in cardiomyocytes induced by H2O2. SiRNA targeted to the urotensin II receptor (UT) greatly inhibited these effects. Further analysis revealed that UII increased the production of hydrogen sulfide (H2S) and the level of cystathionine-γ-lyase (CSE) by activating the ERK signaling in H2O2-treated-cardiomyocytes. Si-CSE or ERK inhibitor not only greatly inhibited the increase in CSE level or the phosphorylation of ERK induced by UII but also reversed anti-apoptosis of UII in H2O2-treated-cadiomyocytes. In conclusion, UII rapidly promoted the phosphorylation of ERK and upregulated CSE level and H2S production, which in turn activated ERK signaling to protect cardiomyocytes from apoptosis under oxidative stress. These results suggest that increased plasma UII level may protect cardiomyocytes at the early-phase of acute myocardial infarction in patients.
doi:10.3390/ijms160612482
PMCID: PMC4490456  PMID: 26047336
urotensin II; apoptosis; cardiomyocyte; cystathionine-γ-lyase (CSE); hydrogen sulfide (H2S)
2.  Renal impairment, hypertension and plasma urotensin II 
Background. Human urotensin II (UII) is a potent mammalian vasoconstrictor thought to be produced and cleared by the kidneys. Conflicting data exist regarding the relationship between UII concentrations, kidney function and blood pressure (BP). We measured the associations between kidney function [including end-stage renal disease (ESRD)] and levels of BP with plasma concentrations of UII.
Methods. Ninety-one subjects were enrolled. Thirty-one subjects had ESRD (undergoing haemodialysis), 30 subjects had chronic kidney disease (CKD) and 30 control subjects had no kidney disease. Plasma UII concentrations were measured by radioimmunoassay.
Results. Mean plasma UII concentrations were highest in controls, lower in subjects with ESRD and lowest in subjects with non-ESRD CKD (P < 0.0001). UII concentrations correlated negatively with serum creatinine (P = 0.0012) and CKD stage, and positively with creatinine clearance (P = 0.013). In ESRD subjects, plasma UII (P = 0.008) increased after dialysis, while SBP (P = 0.007), DBP (P = 0.009), serum creatinine (P < 0.0001) and serum urea nitrogen (P < 0.0001) decreased. UII concentrations were lower in patients with a history of hypertension (HTN) (P = 0.016). Age, race and gender did not appear to be associated with UII concentration. However, the distribution of African American race and male gender appear to be associated with increasing stages of chronic kidney disease.
Conclusions. These data suggest a potential vasodilatory role of UII in humans with kidney disease or hypertension. The reduction in UII levels in CKD also suggests either reduced production or greater clearance, or both, of UII.
doi:10.1093/ndt/gfq416
PMCID: PMC3108358  PMID: 20621933
CKD; diabetes; dialysis; hypertension; urotensin II
3.  Urotensin II in Invertebrates: From Structure to Function in Aplysia californica 
PLoS ONE  2012;7(11):e48764.
Neuropeptides are ancient signaling molecules that are involved in many aspects of organism homeostasis and function. Urotensin II (UII), a peptide with a range of hormonal functions, previously has been reported exclusively in vertebrates. Here, we provide the first direct evidence that UII-like peptides are also present in an invertebrate, specifically, the marine mollusk Aplysia californica. The presence of UII in the central nervous system (CNS) of Aplysia implies a more ancient gene lineage than vertebrates. Using representational difference analysis, we identified an mRNA of a protein precursor that encodes a predicted neuropeptide, we named Aplysia urotensin II (apUII), with a sequence and structural similarity to vertebrate UII. With in-situ hybridization and immunohistochemistry, we mapped the expression of apUII mRNA and its prohormone in the CNS and localized apUII-like immunoreactivity to buccal sensory neurons and cerebral A-cluster neurons. Mass spectrometry performed on individual isolated neurons, and tandem mass spectrometry on fractionated peptide extracts, allowed us to define the posttranslational processing of the apUII neuropeptide precursor and confirm the highly conserved cyclic nature of the mature neuropeptide apUII. Electrophysiological analysis of the central effects of a synthetic apUII suggests it plays a role in satiety and/or aversive signaling in feeding behaviors. Finding the homologue of vertebrate UII in the numerically small CNS of an invertebrate animal model is important for gaining insights into the molecular mechanisms and pathways mediating the bioactivity of UII in the higher metazoan.
doi:10.1371/journal.pone.0048764
PMCID: PMC3493602  PMID: 23144960
4.  Urotensin II in cardiovascular regulation 
Cardiovascular function is modulated by neuronal transmitters, circulating hormones, and factors that are released locally from tissues. Urotensin II (UII) is an 11 amino acid peptide that stimulates its’ obligatory G protein coupled urotensin II receptors (UT) to modulate cardiovascular function in humans and in other animal species, and has been implicated in both vasculoprotective and vasculopathic effects. For example, tissue and circulating concentrations of UII have been reported to increase in some studies involving patients with atherosclerosis, heart failure, hypertension, preeclampsia, diabetes, renal disease and liver disease, raising the possibility that the UT receptor system is involved in the development and/or progression of these conditions. Consistent with this hypothesis, administration of UT receptor antagonists to animal models of cardiovascular disease have revealed improvements in cardiovascular remodelling and hemodynamics. However, recent studies have questioned this contributory role of UII in disease, and have instead postulated a protective effect on the cardiovascular system. For example, high concentrations of circulating UII correlated with improved clinical outcomes in patients with renal disease or myocardial infarction. The purpose of this review is to consider the regulation of the cardiovascular system by UII, giving consideration to methodologies for measurement of plasma concentrations, sites of synthesis and triggers for release.
PMCID: PMC2597773  PMID: 19065995
urotensin II; cardiovascular disease; heart failure; hypertension
5.  A closer look at the role of urotensin II in the metabolic syndrome 
Urotensin II (UII) is a vasoactive peptide that was first discovered in the teleost fish, and later in mammals and humans. UII binds to the G protein coupled receptor GPR14 (now known as UT). UII mediates important physiological and pathological actions by interacting with its receptor. The metabolic syndrome (MetS) is described as cluster of factors such as obesity, dyslipidemia, hypertension, and insulin resistance (IR), further leading to development of type 2 diabetes mellitus and cardiovascular diseases. UII levels are upregulated in patients with the MetS. Evidence directly implicating UII in every risk factor of the MetS has been accumulated. The mechanism that links the different aspects of the MetS relies primarily on IR and inflammation. By directly modulating both of these factors, UII is thought to play a central role in the pathogenesis of the MetS. Moreover, UII also plays an important role in hypertension and hyperlipidemia thereby contributing to cardiovascular complications associated with the MetS.
doi:10.3389/fendo.2012.00165
PMCID: PMC3531708  PMID: 23293629
metabolic syndrome; insulin resistance; inflammation; obesity; dyslipidemia; hypertension; diabetes
6.  Urotensin-II promotes vascular smooth muscle cell proliferation through store-operated calcium entry and EGFR transactivation 
Cardiovascular Research  2013;100(2):297-306.
Aims
Urotensin-II (UII) is a vasoactive peptide that promotes vascular smooth muscle cells (VSMCs) proliferation and is involved in the pathogenesis of atherosclerosis, restenosis, and vascular remodelling. This study aimed to determine the role of calcium (Ca2+)-dependent signalling and alternative signalling pathways in UII-evoked VSMCs proliferation focusing on store-operated Ca2+ entry (SOCE) and epithelium growth factor receptor (EGFR) transactivation.
Methods and results
We used primary cultures of VSMCs isolated from Wistar rat aorta to investigate the effects of UII on intracellular Ca2+ mobilization, and proliferation determined by the 5-bromo-2-deoxyuridine (BrdU) assay. We found that UII enhanced intracellular Ca2+ concentration ([Ca2+]i) which was significantly reduced by classical SOCE inhibitors and by knockdown of essential components of the SOCE such as stromal interaction molecule 1 (STIM1), Orai1, or TRPC1. Moreover, UII activated a Gd3+-sensitive current with similar features of the Ca2+ release-activated Ca2+ current (ICRAC). Additionally, UII stimulated VSMCs proliferation and Ca2+/cAMP response element-binding protein (CREB) activation through the SOCE pathway that involved STIM1, Orai1, and TRPC1. Co-immunoprecipitation experiments showed that UII promoted the association between Orai1 and STIM1, and between Orai1 and TRPC1. Moreover, we determined that EGFR transactivation, extracellular signal-regulated kinase (ERK) and Ca2+/calmodulin-dependent kinase (CaMK) signalling pathways were involved in both UII-mediated Ca2+ influx, CREB activation and VSMCs proliferation.
Conclusion
Our data show for the first time that UII-induced VSMCs proliferation and CREB activation requires a complex signalling pathway that involves on the one hand SOCE mediated by STIM1, Orai1, and TRPC1, and on the other hand EGFR, ERK, and CaMK activation.
doi:10.1093/cvr/cvt196
PMCID: PMC3797630  PMID: 23933581
Smooth muscle; Proliferation; Ion channels; EGFR
7.  Urotensin II Promotes Atherosclerosis in Cholesterol-Fed Rabbits 
PLoS ONE  2014;9(4):e95089.
Urotensin II (UII) is a vasoactive peptide composed of 11 amino acids that has been implicated to contribute to the development of cardiovascular disease. The purpose of this study was to investigate whether UII affects the development of atherosclerosis in cholesterol-fed rabbits. UII was infused for 16 weeks through an osmotic mini-pump into male Japanese White rabbits fed on a high-cholesterol diet. Plasma lipids and body weight were measured every 4 weeks. Aortic atherosclerotic lesions along with cellular components, collagen fibers, matrix metalloproteinase-1 and -9 were examined. Moreover, vulnerability index of atherosclerotic plaques was evaluated. UII infusion significantly increased atherosclerotic lesions within the entire aorta by 21% over the control (P = 0.013). Atherosclerotic lesions were increased by 24% in the aortic arch (P = 0.005), 11% in the thoracic aorta (P = 0.054) and 18% in the abdominal aorta (P = 0.035). These increases occurred without changes in plasma levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides or body weight. Immunohistochemical staining revealed that macrophages and matrix metalloproteinase-9 were significantly enhanced by 2.2-fold and 1.6-fold in UII group. In vitro studies demonstrated that UII up-regulated the expression of vascular cell adhesion protein-1 and intercellular adhesion molecule-1 in human umbilical vein endothelial cells, which was inhibited by the UII receptor antagonist urantide. In conclusion, our results showed that UII promotes the development of atherosclerotic lesions and destabilizes atherosclerotic plaques in cholesterol-fed rabbits.
doi:10.1371/journal.pone.0095089
PMCID: PMC3991611  PMID: 24747943
8.  Protein expression of urotensin II, urotensin-related peptide and their receptor in the lungs of patients with lymphangioleiomyomatosis 
Peptides  2010;31(8):1511-1516.
Urotensin II (UII) and urotensin-related peptide (URP) are vasoactive neuropeptides with wide ranges of action in the normal mammalian lung, including the control of smooth muscle cell proliferation. UII and URP exert their actions by binding to the G-protein coupled receptor-14 known as UT. Lymphangioleiomyomatosis (LAM) is a disease of progressive lung destruction resulting from the excessive growth of abnormal smooth muscle-like cells that exhibit markers of neural crest origin. LAM cells also exhibit inactivation of the tumor suppressor tuberin (TSC2), excessive activity of ‘mammalian target of rapamycin (mTOR), and dysregulated cell growth and proliferation. In the present study we examined the expression and distribution of U-II and UT in the lungs of patients with LAM. There was abundant expression of UII, URP and UT proteins in the interstitial nodular lesions of patients with LAM. By immunohistochemistry, UII, URP and UT were co-localized with HMB45, a diagnostic marker of LAM. Immunoreactivity for UII, URP and UT was also evident over the pulmonary epithelium, pulmonary vasculature and inflammatory cells. Western blotting revealed the presence of greater UT expression in the lungs of patients with LAM compared to normal human lungs. UT expression correlated with mTOR activity, as indicated by increased phosphorylation of S6 in LAM samples. These findings demonstrate for the first time the presence of UII, URP and their receptor in the lesions of patients with LAM, and suggest a possible role in the pathogenesis of the disease.
doi:10.1016/j.peptides.2010.04.017
PMCID: PMC2905484  PMID: 20433884
9.  Down-Regulation of GABAA Receptor via Promiscuity with the Vasoactive Peptide Urotensin II Receptor. Potential Involvement in Astrocyte Plasticity 
PLoS ONE  2012;7(5):e36319.
GABAA receptor (GABAAR) expression level is inversely correlated with the proliferation rate of astrocytes after stroke or during malignancy of astrocytoma, leading to the hypothesis that GABAAR expression/activation may work as a cell proliferation repressor. A number of vasoactive peptides exhibit the potential to modulate astrocyte proliferation, and the question whether these mechanisms may imply alteration in GABAAR-mediated functions and/or plasma membrane densities is open. The peptide urotensin II (UII) activates a G protein-coupled receptor named UT, and mediates potent vasoconstriction or vasodilation in mammalian vasculature. We have previously demonstrated that UII activates a PLC/PIPs/Ca2+ transduction pathway, via both Gq and Gi/o proteins and stimulates astrocyte proliferation in culture. It was also shown that UT/Gq/IP3 coupling is regulated by the GABAAR in rat cultured astrocytes. Here we report that UT and GABAAR are co-expressed in cerebellar glial cells from rat brain slices, in human native astrocytes and in glioma cell line, and that UII inhibited the GABAergic activity in rat cultured astrocytes. In CHO cell line co-expressing human UT and combinations of GABAAR subunits, UII markedly depressed the GABA current (β3γ2>α2β3γ2>α2β1γ2). This effect, characterized by a fast short-term inhibition followed by drastic and irreversible run-down, is not relayed by G proteins. The run-down partially involves Ca2+ and phosphorylation processes, requires dynamin, and results from GABAAR internalization. Thus, activation of the vasoactive G protein-coupled receptor UT triggers functional inhibition and endocytosis of GABAAR in CHO and human astrocytes, via its receptor C-terminus. This UII-induced disappearance of the repressor activity of GABAAR, may play a key role in the initiation of astrocyte proliferation.
doi:10.1371/journal.pone.0036319
PMCID: PMC3341351  PMID: 22563490
10.  Divergent cardio-ventilatory and locomotor effects of centrally and peripherally administered urotensin II and urotensin II-related peptides in trout 
The urotensin II (UII) gene family consists of four paralogous genes called UII, UII-related peptide (URP), URP1 and URP2. UII and URP peptides exhibit the same cyclic hexapeptide core sequence (CFWKYC) while the N- and C-terminal regions are variable. UII, URP1, and URP2 mRNAs are differentially expressed within the central nervous system of teleost fishes, suggesting that they may exert distinct functions. Although the cardiovascular, ventilatory and locomotor effects of UII have been described in teleosts, much less is known regarding the physiological actions of URPs. The goal of the present study was to compare the central and peripheral actions of picomolar doses (5–500 pmol) of trout UII, URP1, and URP2 on cardio-ventilatory variables and locomotor activity in the unanesthetized trout. Compared to vehicle, intracerebroventricular injection of UII, URP1 and URP2 evoked a gradual increase in total ventilation (VTOT) reaching statistical significance for doses of 50 and 500 pmol of UII and URP1 but for only 500 pmol of URP2. In addition, UII, URP1 and URP2 provoked an elevation of dorsal aortic blood pressure (PDA) accompanied with tachycardia. All peptides caused an increase in locomotor activity (ACT), at a threshold dose of 5 pmol for UII and URP1, and 50 pmol for URP2. After intra-arterial (IA) injection, and in contrast to their central effects, only the highest dose of UII and URP1 significantly elevated VTOT and ACT. UII produced a dose-dependent hypertensive effect with concomitant bradycardia while URP1 increased PDA and heart rate after injection of only the highest dose of peptide. URP2 did not evoke any cardio-ventilatory or locomotor effect after IA injection. Collectively, these findings support the hypothesis that endogenous UII, URP1 and URP2 in the trout brain may act as neurotransmitters and/or neuromodulators acting synergistically or differentially to control the cardio-respiratory and locomotor systems. In the periphery, the only physiological actions of these peptides might be those related to the well-known cardiovascular regulatory actions of UII. It remains to determine whether the observed divergent physiological effects of UII and URPs are due to differential interaction with the UT receptor or binding to distinct UT subtypes.
doi:10.3389/fnins.2015.00142
PMCID: PMC4406059  PMID: 25954149
urotensin II; urotensin II-related peptides; ventilatory variables; heart rate; blood pressure; locomotor activity; brain; trout
11.  Value of N-terminal pro brain natriuretic peptide in predicting prognosis and severity of coronary artery disease in acute coronary syndrome 
Background
Measurement of N-terminal pro brain natriuretic peptide (NT-proBNP) in the evaluation of patients with acute coronary syndrome has appeared to be a useful prognostic marker of cardiovascular risk.
Aim of the work
To assess the in-hospital prognostic value of NT-proBNP in patients with acute coronary syndrome (ACS) and its relation to the severity of coronary artery disease.
Patients and methods
This study included 132 consecutive patients with ACS, 64 patients with unstable angina (UA), 46 patients with non-ST segment elevation myocardial infarction (NSTEMI), and 22 patients with ST segment elevation myocardial infarction (STEMI). ECG, echocardiography and pre and post coronary angiography measurement of troponin I, creatine kinase (Ck), C-reactive protein (CRP) and NT-proBNP were done. Patients were divided into two groups: Group A with NT-proBNP less than 474 pg/ml and Group B with NT-proBNP equal or more than 474 pg/ml.
Results
There was a significant negative correlation between NT-proBNP and ejection fraction. Incidence of heart failure and duration of hospital stay were significantly higher in Group B (with NT-proBNP equal or more than 474 pg/ml) than Group A (with NT-proBNP less than 474 pg/ml). Moreover, there was a trend to an increased incidence of cardiogenic shock and mortality in Group B compared to Group A. The number of coronary vessels affected, severity of stenosis and proximal left anterior descending artery (LAD) disease were higher in Group B than in Group A. TIMI flow grade was significantly higher in Group A than in Group B.
Conclusion
NT-proBNP is a valuable marker for predicting prognosis and severity of coronary artery disease in patients with acute coronary syndrome.
doi:10.1016/j.jsha.2014.04.004
PMCID: PMC4179900  PMID: 25278720
Brain natriuretic peptid; Coronary artery disease; Acute coronary syndrome
12.  Discovery of new antagonists aimed at discriminating UII and URP-mediated biological activities: insight into UII and URP receptor activation 
British Journal of Pharmacology  2013;168(4):807-821.
Background and Purpose
Recent evidence suggested that urotensin II (UII) and its paralog peptide UII-related peptide (URP) might exert common but also divergent physiological actions. Unfortunately, none of the existing antagonists were designed to discriminate specific UII- or URP-associated actions, and our understanding, on how these two endogenous peptides can trigger different, but also common responses, is limited.
Experimental Approach
Ex vivo rat and monkey aortic ring contraction as well as dissociation kinetics studies using transfected CHO cells expressing the human urotensin (UT) receptors were used in this study.
Key Results
Ex vivo rat and monkey aortic ring contraction studies revealed the propensity of [Pep4]URP to decrease the maximal response of human UII (hUII) without any significant change in potency, whereas no effect was noticeable on the URP-induced vasoconstriction. Dissociation experiments demonstrated the ability of [Pep4]URP to increase the dissociation rate of hUII, but not URP. Surprisingly, URP, an equipotent UII paralog, was also able to accelerate the dissociation rate of membrane-bound 125I-hUII, whereas hUII had no noticeable effect on URP dissociation kinetics. Further experiments suggested that an interaction between the glutamic residue at position 1 of hUII and the UT receptor seems to be critical to induce conformational changes associated with agonistic activation. Finally, we demonstrated that the N-terminal domain of the rat UII isoform was able to act as a specific antagonist of the URP-associated actions.
Conclusion
Such compounds, that is [Pep4]URP and rUII(1–7), should prove to be useful as new pharmacological tools to decipher the specific role of UII and URP in vitro but also in vivo.
doi:10.1111/j.1476-5381.2012.02217.x
PMCID: PMC3631372  PMID: 22994258
urotensin II; urotensin II-related peptide; insurmountable antagonism; GPCR; human UT receptors; aortic ring bioassay
13.  Urotensin II contributes to the formation of lung adenocarcinoma inflammatory microenvironment through the NF-κB pathway in tumor-bearing nude mice 
Oncology Letters  2012;4(6):1259-1263.
Urotensin II (UII), a somatostatin-like cyclic peptide, was originally isolated from the fish urophysis. Our previous study showed that UII stimulates the proliferation of A549 lung adenocarcinoma cells and promotes tumor growth in a nude mouse xenograft model, suggesting that UII may contribute to the pathogenesis of lung adenocarcinoma. In this study, the underlying mechanism for UII to promote lung adenocarcinoma growth was explored by observing the effect of UII on the tumor inflammatory microenvironment in tumor-bearing nude mice. Immunohistochemical analysis showed that UII promoted the infiltration of CD68+ tumor-associated macrophages (TAMs) in the tumor micro-environment. Enzyme-linked immunosorbent assay (ELISA) demonstrated that UII promoted the release of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and matrix metalloproteinase-9 (MMP-9). Western blot analysis showed that UII promoted the activation of nuclear factor-κB (NF-κB). These findings suggest that the enhanced levels of IL-6, TNF-α and MMP-9 in the tumor microenvironment, which likely resulted from increased activation of NF-κB induced by UII, may be one of the important mechanisms by which UII promotes lung adenocarcinoma growth. These findings imply that antagonists of UII or urotensin II-receptor (UT-R) have potential for the prevention and treatment of lung adenocarcinoma.
doi:10.3892/ol.2012.932
PMCID: PMC3506729  PMID: 23226801
urotensin II; lung adenocarcinoma; inflammatory microenvironment; nude mice
14.  Urotensin-II Immunoreactivity in Normolipidemic and Hyperlipidemic New Zealand White Rabbits Following Balloon Angioplasty and Stenting 
Treatment for symptomatic atherosclerosis is being carried out by balloon mediated angioplasty, with or without stent implantation, more and more frequently. Although advances with the development of drug eluting stents have improved prognosis, restenosis is still the most limiting factor for this treatment modality. Urotensin-II (UII), a small pleiotropic vasoactive peptide is increasingly being recognized as a contributory factor in cardiovascular diseases. We qualitatively evaluated UII immunoreactivity (IR) in three models of balloon angioplasty mediated restenosis. Specifically, we performed balloon angioplasty in the ilio-femoral arteries of New Zealand White Rabbits (NZWR) fed either a normal chow or high fat diet. In addition, UIIIR was also assessed in stent implanted abdominal aortae of NZWR fed a high fat diet. UII was constitutively expressed in the endothelium of all arterial segments evaluated. Abundant expression of UII was associated with lesion progression, particularly in myointimal cells, and less so in medial smooth muscle cells (SMC). The strongest UII-IR was observed in foam cells of animals fed a high fat diet. We demonstrate abundant expression of UII in regenerating endothelial cells and myointimal cells in vascular lesions following balloon mediated angioplasty and stent implantation in both animals fed a normal chow and high fat diet.
PMCID: PMC3614616  PMID: 23675019
endothelium; immunohistochemistry; vascular injury; peptide
15.  Vasoconstrictive effects of endothelin-1, endothelin-3, and urotensin II in isolated perfused human lungs and isolated human pulmonary arteries 
Thorax  2004;59(5):401-407.
Background: Urotensin II (UII) has been identified as a ligand for the orphan receptor GPR14 through which it elicits potent vasoconstriction in humans and non-human primates. The pulmonary vasculature is particularly sensitive; human UII (hUII) exhibits a potency 28 times that of endothelin (ET)-1 in isolated pulmonary arteries obtained from cynomolgus monkeys. However, hUII induced vasoconstriction in isolated human intralobar pulmonary arteries is variable, possibly as a result of location dependent differences in receptor density or because it is only uncovered by disease dependent endothelial dysfunction.
Methods: The vasoactivity of both hUII and gobi UII (gUII) in comparison with ET-1 and ET-3 was studied in isolated perfused lung preparations (n = 14) and isolated intralobar pulmonary arteries (n = 40, mean diameter 548 (27) µm) obtained from 17 men of mean (SE) age 67 (2) years and eight women of mean (SE) age 65 (3) years with a variety of vascular diseases.
Results: ET-1 (10 pM–100 nM) and ET-3 (10 pM–30 nM) elicited vasoconstriction in the lung preparations, inducing comparable increases in pulmonary arterial pressure of 24.8 (4.5) mm Hg and 14.5 (4.9) mm Hg, respectively, at 30 nM (p = 0.13). Similarly, ET-1 (10 pM–300 nM) and ET-3 (10 pM–100 nM) caused marked vasoconstriction in isolated pulmonary arteries, inducing maximal changes in tension of 4.36 (0.26) mN/mm and 1.54 (0.44) mN/mm, respectively, generating –logEC50 values of 7.67 (0.04) M and 8.08 (0.07) M, respectively (both p<0.05). However, neither hUII nor gUII (both 10 pM–1 µM) had any vasoactive effect in either preparation.
Conclusion: UII does not induce vasoconstriction in isolated human pulmonary arterial or lung preparations and is therefore unlikely to be involved in the control of pulmonary vascular tone.
doi:10.1136/thx.2003.011197
PMCID: PMC1747004  PMID: 15115867
16.  Urotensin II inhibited the proliferation of cardiac side population cells in mice during pressure overload by JNK-LRP6 signalling 
Cardiac side population cells (CSPs) are promising cell resource for the regeneration in diseased heart as intrinsic cardiac stem cells. However, the relative low ratio of CSPs in the heart limited the ability of CSPs to repair heart and improve cardiac function effectively under pathophysiological condition. Which factors limiting the proliferation of CSPs in diseased heart are unclear. Here, we show that urotensin II (UII) regulates the proliferation of CSPs by c-Jun N-terminal kinase (JNK) and low density lipoprotein receptor-related protein 6 (LRP6) signalling during pressure overload. Pressure overload greatly upregulated UII level in plasma, UII receptor (UT) antagonist, urantide, promoted CSPs proliferation and improved cardiac dysfunction during chronic pressure overload. In cultured CSPs subjected to mechanical stretch (MS), UII significantly inhibited the proliferation by UT. Nanofluidic proteomic immunoassay showed that it is the JNK activation, but not the extracellular signal-regulated kinase signalling, that involved in the UII-inhibited- proliferation of CSPs during pressure overload. Further analysis in vitro indicated UII-induced-phospho-JNK regulates phosphorylation of LRP6 in cultured CSPs after MS, which is important in the inhibitory effect of UII on the CSPs during pressure overload. In conclusion, UII inhibited the proliferation of CSPs by JNK/LRP6 signalling during pressure overload. Pharmacological inhibition of UII promotes CSPs proliferation in mice, offering a possible therapeutic approach for cardiac failure induced by pressure overload.
doi:10.1111/jcmm.12230
PMCID: PMC4119391  PMID: 24447593
Urotensin II; CSPs; proliferation; JNK; LRP6
17.  Inhibition of UII/UTR System Relieves Acute Inflammation of Liver through Preventing Activation of NF-κB Pathway in ALF Mice 
PLoS ONE  2013;8(6):e64895.
Urotensin II (UII) is implicated in immune inflammatory diseases through its specific high-affinity UT receptor (UTR). Enhanced expression of UII/UTR was recently demonstrated in the liver with acute liver failure (ALF). Here, we analysed the relationship between UII/UTR expression and ALF in lipopolysaccharide (LPS)/D-galactosamine (GalN)-challenged mice. Thereafter, we investigated the effects produced by the inhibition of UII/UTR system using urantide, a special antagonist of UTR, and the potential molecular mechanisms involved in ALF. Urantide was administered to mice treated with LPS/GalN. Expression of UII/UTR, releases of proinflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and interferon-γ (IFN-γ), and activation of nuclear factor κB (NF-κB) signaling pathway were assessed in the lethal ALF with or without urantide pretreatment. We found that LPS/GalN-challenged mice showed high mortality and marked hepatic inflammatory infiltration and cell apoptosis as well as a significant increase of UII/UTR expression. Urantide pretreatment protected against the injury in liver following downregulation of UII/UTR expression. A close relationship between the acutely flamed hepatic injury and UII/UTR expression was observed. In addition, urantide prevented the increases of proinflammatory cytokines such as TNF-α, IL-1β and IFN-γ, and activation of NF-κB signaling pathway induced by LPS/GalN in mice. Thus, we conclude that UII/UTR system plays a role in LPS/GalN-induced ALF. Urantide has a protective effect on the acutely inflamed injury of liver in part through preventing releases of proinflammatory cytokines and activation of NF-κB pathway.
doi:10.1371/journal.pone.0064895
PMCID: PMC3670940  PMID: 23755157
18.  Effects of urotensin-II on cytokines in early acute liver failure in mice 
AIM: To investigate urotensin-II (UII) and its effects on tumor necrosis factor (TNF)-α and interleukin (IL)-1β in early acute liver failure (ALF).
METHODS: We investigated the time-dependent alteration in UII levels and its effects on TNF-α and IL-1β in liver and blood in the early stage of lipopolysaccharide/D-galactosamine-induced ALF.
RESULTS: After lipopolysaccharide/D-galactosamine challenge, UII rose very rapidly and reached a maximal level 0.5 h, and the level remained significantly elevated after 2 h (P < 0.05). Six hours after challenge, UII began to degrade, but remained higher than at 0 h (P < 0.05). Pretreatment with urantide, an inhibitor of the UII receptor, suppressed the degree of UII increase in liver and blood at 6 h after challenge (P < 0.05 vs paired controls). In addition, liver and blood TNF-α increased from 1 to 6 h, and reached a peak at 1 and 2 h, respectively; however, IL-1β did not rise until 6 h after challenge. Urantide pretreatment inhibited the degree of TNF-α and IL-1β increase following downregulation of UII post-challenge (all P < 0.05).
CONCLUSION: UII plays a role in the pathogenesis and priming of ALF by triggering an inflammatory cascade and driving the early release of cytokines in mice.
doi:10.3748/wjg.v21.i11.3239
PMCID: PMC4363753  PMID: 25805930
Acute hepatic failure; Interleukin-1β; Mouse; Tumor necrosis factor α; Urantide; Urotensin-II
19.  The Urotensin System Is Up-Regulated in the Pre-Hypertensive Spontaneously Hypertensive Rat 
PLoS ONE  2013;8(12):e83317.
Urotensin II (UII) concentrations are raised both in humans with hypertension and in spontaneously hypertensive rats (SHR). Since the urotensin system acts to regulate glomerular filtration in the kidney it may play a greater role in the pre-hypertensive SHR in which renal dysfunction is known to precede the onset of severe hypertension. This study aimed to determine the renal actions and expression of the urotensin system in the young SHR. Intravenous rat UII (6 pmol. min-1. 100 g body weight-1) had no significant effect on GFR; however urotensin-related peptide (URP) reduced GFR (P<0.05) in 4-5 week old SHR. Administration of the UT antagonist SB-706375 evoked marked increases in GFR (baseline 0.38 ± 0.07 vs antagonist 0.76 ± 0.05 ml. min-1. 100 g body weight-1, P<0.05), urine flow and sodium excretion (baseline 2.5 ± 0.4 vs antagonist 9.1 ± 2.1 µmol. min-1. 100 g body weight-1, P<0.05) in the SHR. Normotensive Wistar-Kyoto rats showed little response to UT antagonism. Quantitative RT-PCR showed that neither UII nor UT mRNA expression differed between the kidneys of young SHR and WKY rats; however expression of URP was 4-fold higher in the SHR kidney. Renal transcriptional up-regulation indicates that URP is the major UT ligand in young SHR and WKY rats. Enhanced tonic UT activation may contribute to known renal dysfunction in pre-hypertensive SHR.
doi:10.1371/journal.pone.0083317
PMCID: PMC3855556  PMID: 24340095
20.  Urotensin II Inhibits Skeletal Muscle Glucose Transport Signaling Pathways via the NADPH Oxidase Pathway 
PLoS ONE  2013;8(10):e76796.
Our previous studies have demonstrated that the urotensin (UII) and its receptor are up-regulated in the skeletal muscle of mice with type II diabetes mellitus (T2DM), but the significance of UII in skeletal muscle insulin resistance remains unknown. The purpose of this study was to investigate the effect of UII on NADPH oxidase and glucose transport signaling pathways in the skeletal muscle of mice with T2DM and in C2C12 mouse myotube cells. KK/upj-AY/J mice (KK) mice were divided into the following groups: KK group, with saline treatment for 2 weeks; KK+ urantide group, with daily 30 µg/kg body weight injections over the same time period of urantide, a potent urotensin II antagonist peptide; Non-diabetic C57BL/6J mice were used as normal controls. After urantide treatment, mice were subjected to an intraperitoneal glucose tolerance test, in addition to measurements of the levels of ROS, NADPH oxidase and the phosphorylated AKT, PKC and ERK. C2C12 cells were incubated with serum-free DMEM for 24 hours before conducting the experiments, and then administrated with 100 nM UII for 2 hours or 24 hours. Urantide treatment improved glucose tolerance, decreased the translocation of the NADPH subunits p40-phox and p47-phox, and increased levels of the phosphorylated PKC, AKT and ERK. In contrast, UII treatment increased ROS production and p47-phox and p67-phox translocation, and decreased the phosphorylated AKT, ERK1/2 and p38MAPK; Apocynin abrogated this effect. In conclusion, UII increased ROS production by NADPH oxidase, leading to the inhibition of signaling pathways involving glucose transport, such as AKT/PKC/ERK. Our data imply a role for UII at the molecular level in glucose homeostasis, and possibly in skeletal muscle insulin resistance in T2DM.
doi:10.1371/journal.pone.0076796
PMCID: PMC3792887  PMID: 24116164
21.  Is a Pattern of Increasing Biomarker Concentrations Important for Long-Term Risk Stratification in Acute Coronary Syndrome Patients Presenting Early after the Onset of Symptoms? 
Clinical chemistry  2008;54(4):747-751.
BACKGROUND
Guidelines for treatment of acute coronary syndrome (ACS) recommend observing a rise or fall in cardiac troponin (cTn) concentrations for assessing acute injury. It is unknown whether a rising pattern presages a more adverse long-term prognosis than elevations that do not change. The present study assessed whether a rising pattern of cardiac biomarkers was more prognostic than simple elevations.
METHODS
We measured N-terminal pro-brain natriuretic peptide (NT-proBNP) (Roche), cTnT (Roche) and cTnI (Beckman Coulter) in 212 ACS patients. These biomarkers were measured in coincident EDTA and heparin plasma samples available from at least 2 different time points, an early first specimen obtained a median of 2 hours after onset of symptoms, interquartile range (IQR) 2– 4 hours, and a later second specimen obtained at 9 hours, IQR 9 –9 hours. The cTn concentration in the second specimen was used to classify myocardial necrosis (cTnI >0.04 ug/L; cTnT >0.01 ug/L). Outcomes [death, myocardial infarction (MI), heart failure (HF)] were obtained >8 years after the initial presentation. For patients with myocardial necrosis and a cTn concentration ratio (second/first measured concentrations) ≥1.00, the concentration ratios and the absolute concentrations in the second specimen were used to assess prognosis after 4 years.
RESULTS
In myocardial necrosis, the relative change (cTn2/cTn1) was greater for cTnI than for cTnT (P <0.01), whereas the relative change in NT-proBNP was the same regardless of which troponin was used to classify necrosis (P =0.71). The concentration ratio for cTnI, cTnT, and NT-proBNP was not useful for risk stratification (i.e., death/MI/HF; P ≥0.15).
CONCLUSIONS
A rise in cardiac troponin or NT-proBNP concentration in ACS patients presenting early after onset of pain is not helpful for long-term prognosis.
doi:10.1373/clinchem.2007.094664
PMCID: PMC3569503  PMID: 18375487 CAMSID: cams2709
22.  The UII/UT System Mediates Upregulation of Proinflammatory Cytokines through p38 MAPK and NF-κB Pathways in LPS-Stimulated Kupffer Cells 
PLoS ONE  2015;10(3):e0121383.
The urotensin II (UII)/UII receptor (UT) system is closely related to immune inflammation. In acute liver failure (ALF), the UII/UT system can promote the production and release of proinflammatory cytokines, inducing an inflammatory injury response in liver tissue. However, the mechanism by which the hepatic UII/UT system promotes proinflammatory cytokine production and release is not clear. To solve this problem, we used primary Kupffer cells (KCs) as the model system in the current study. The results showed that after lipopolysaccharide (LPS) stimulation, KCs showed significantly increased expression and release of UII/UT and proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). Pretreatment with urantide, which is a UT receptor antagonist, significantly inhibited the LPS-stimulated expression and release of UII/UT, TNF-α, and IL-1β by KCs. In addition, LPS stimulation induced nuclear p38 mitogen-activated protein kinase (MAPK) protein phosphorylation and expression of the nuclear nuclear factor κB (NF-κB) p65 subunit in KCs and enhanced the binding activity of NF-κB to DNA molecules, whereas urantide pretreatment significantly inhibited the LPS-stimulated nuclear expression and activity of these molecules in KCs. Therefore, our conclusion is that the UII/UT system mediates LPS-stimulated production and release of proinflammatory cytokine by KCs, and this mediating effect at least partially relies on the inflammatory signaling pathway molecules p38 MAPK and NF-κB.
doi:10.1371/journal.pone.0121383
PMCID: PMC4372515  PMID: 25803040
23.  Effect of urotensin II on apolipoprotein B100 and apolipoprotein A-I expression in HepG2 cell line 
Background:
Increased apolipoprotein B100 (apo B) and decreased apolipoprotein A-I (apo A-I) production are important risk factors in atherosclerosis. Urotensin II (UII), as the most potent vasoconstrictor in human, is related with hypertension and probably atherosclerosis. Because of the relationship between the hypertension and lipoprotein metabolism in atherosclerosis, the aim of this study was to test the effect of urotensin II on apo B and apo A-I expression in hepatic (HepG2) cell line.
Materials and Methods:
HepG2 cells were treated with 10, 50, 100, and 200 nmol/L of urotensin II (n = 6). Relative apo B and apo A-I messenger RNA (mRNA) levels in conditioned media, normalized to glyceraldehyde-3-phosphate dehydrogenase, were measured with quantitative real-time polymerase chain reaction method. In addition, apo B and apo A-I levels were also estimated and compared with the controls using the western blotting method. Data were analyzed statistically by ANOVA and non-parametric tests.
Results:
The apo B mRNA levels were not increased significantly following the treatment with UII. However, apo B protein levels were increased significantly after the treatment with urotensin II, especially at 100 and 200 nmol/L. The apo A-I mRNA and protein levels in conditioned media also were not significantly changed. However, there was a significant decrease in apo A-I mRNA and protein levels at 200 nM UII.
Conclusions:
UII might increase apo B at protein level probably through participating factors in its synthesis and/ or stability/degradation. In addition, UII may have decreasing effect at more than 200 nM concentrations on apo A-I.
doi:10.4103/2277-9175.124661
PMCID: PMC3929015  PMID: 24600602
Apolipoprotein B100; apolipoprotein A-I; expression; HepG2; urotensin II
24.  Comparative Distribution and In Vitro Activities of the Urotensin II-Related Peptides URP1 and URP2 in Zebrafish: Evidence for Their Colocalization in Spinal Cerebrospinal Fluid-Contacting Neurons 
PLoS ONE  2015;10(3):e0119290.
Urotensin II (UII) is an evolutionarily conserved neuropeptide initially isolated from teleost fish on the basis of its smooth muscle-contracting activity. Subsequent studies have demonstrated the occurrence of several UII-related peptides (URPs), such that the UII family is now known to include four paralogue genes called UII, URP, URP1 and URP2. These genes probably arose through the two rounds of whole genome duplication that occurred during early vertebrate evolution. URP has been identified both in tetrapods and teleosts. In contrast, URP1 and URP2 have only been observed in ray-finned and cartilaginous fishes, suggesting that both genes were lost in the tetrapod lineage. In the present study, the distribution of urp1 mRNA compared to urp2 mRNA is reported in the central nervous system of zebrafish. In the spinal cord, urp1 and urp2 mRNAs were mainly colocalized in the same cells. These cells were also shown to be GABAergic and express the gene encoding the polycystic kidney disease 2-like 1 (pkd2l1) channel, indicating that they likely correspond to cerebrospinal fluid-contacting neurons. In the hindbrain, urp1-expressing cells were found in the intermediate reticular formation and the glossopharyngeal-vagal motor nerve nuclei. We also showed that synthetic URP1 and URP2 were able to induce intracellular calcium mobilization in human UII receptor (hUT)-transfected CHO cells with similar potencies (pEC50=7.99 and 7.52, respectively) albeit at slightly lower potencies than human UII and mammalian URP (pEC50=9.44 and 8.61, respectively). The functional redundancy of URP1 and URP2 as well as the colocalization of their mRNAs in the spinal cord suggest the robustness of this peptidic system and its physiological importance in zebrafish.
doi:10.1371/journal.pone.0119290
PMCID: PMC4364556  PMID: 25781313
25.  Update on the urotensinergic system: new trends in receptor localization, activation, and drug design 
The urotensinergic system plays central roles in the physiological regulation of major mammalian organ systems, including the cardiovascular system. As a matter of fact, this system has been linked to numerous pathophysiological states including atherosclerosis, heart failure, hypertension, diabetes as well as psychological, and neurological disorders. The delineation of the (patho)physiological roles of the urotensinergic system has been hampered by the absence of potent and selective antagonists for the urotensin II-receptor (UT). Thus, a more precise definition of the molecular functioning of the urotensinergic system, in normal conditions as well as in a pathological state is still critically needed. The recent discovery of nuclear UT within cardiomyocytes has highlighted the cellular complexity of this system and suggested that UT-associated biological responses are not only initiated at the cell surface but may result from the integration of extracellular and intracellular signaling pathways. Thus, such nuclear-localized receptors, regulating distinct signaling pathways, may represent new therapeutic targets. With the recent observation that urotensin II (UII) and urotensin II-related peptide (URP) exert different biological effects and the postulate that they could also have distinct pathophysiological roles in hypertension, it appears crucial to reassess the recognition process involving UII and URP with UT, and to push forward the development of new analogs of the UT system aimed at discriminating UII- and URP-mediated biological activities. The recent development of such compounds, i.e. urocontrin A and rUII(1–7), is certainly useful to decipher the specific roles of UII and URP in vitro and in vivo. Altogether, these studies, which provide important information regarding the pharmacology of the urotensinergic system and the conformational requirements for binding and activation, will ultimately lead to the development of potent and selective drugs.
doi:10.3389/fendo.2012.00174
PMCID: PMC3533682  PMID: 23293631
urotensin II; urotensin II-related peptide; allosteric modulation; biased agonist; nuclear receptors

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