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1.  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.
PMCID: PMC3108358  PMID: 20621933
CKD; diabetes; dialysis; hypertension; urotensin II
2.  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.
PMCID: PMC3493602  PMID: 23144960
3.  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
4.  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.
PMCID: PMC3531708  PMID: 23293629
metabolic syndrome; insulin resistance; inflammation; obesity; dyslipidemia; hypertension; diabetes
5.  Urotensin-II promotes vascular smooth muscle cell proliferation through store-operated calcium entry and EGFR transactivation 
Cardiovascular Research  2013;100(2):297-306.
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.
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.
PMCID: PMC3797630  PMID: 23933581
Smooth muscle; Proliferation; Ion channels; EGFR
6.  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.
PMCID: PMC3991611  PMID: 24747943
7.  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.
PMCID: PMC2905484  PMID: 20433884
8.  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.
PMCID: PMC3341351  PMID: 22563490
9.  Value of N-terminal pro brain natriuretic peptide in predicting prognosis and severity of coronary artery disease in acute coronary syndrome 
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.
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.
NT-proBNP is a valuable marker for predicting prognosis and severity of coronary artery disease in patients with acute coronary syndrome.
PMCID: PMC4179900  PMID: 25278720
Brain natriuretic peptid; Coronary artery disease; Acute coronary syndrome
10.  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.
PMCID: PMC3506729  PMID: 23226801
urotensin II; lung adenocarcinoma; inflammatory microenvironment; nude mice
11.  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
12.  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.
PMCID: PMC1747004  PMID: 15115867
13.  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.
PMCID: PMC4119391  PMID: 24447593
Urotensin II; CSPs; proliferation; JNK; LRP6
14.  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.
PMCID: PMC3670940  PMID: 23755157
15.  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.
PMCID: PMC3855556  PMID: 24340095
16.  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.
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.
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.
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).
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.
PMCID: PMC3569503  PMID: 18375487 CAMSID: cams2709
17.  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.
PMCID: PMC3792887  PMID: 24116164
18.  Effect of urotensin II on apolipoprotein B100 and apolipoprotein A-I expression in HepG2 cell line 
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.
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.
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.
PMCID: PMC3929015  PMID: 24600602
Apolipoprotein B100; apolipoprotein A-I; expression; HepG2; urotensin II
19.  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.
PMCID: PMC3533682  PMID: 23293631
urotensin II; urotensin II-related peptide; allosteric modulation; biased agonist; nuclear receptors
20.  Urotensin I–CRF–Urocortins: A mermaid’s tail 
From the individual perspective of the two authors who were long-time colleagues of Karl Lederis at the University of Calgary, the events and personal interactions are described, that are relevant to the discovery of Urotensin I (UI) in the Lederis laboratory, along with the concurrent discovery of Urotensin II (UII) in the Bern laboratory and corticotropin-releasing factor (CRF/CRH) in the Vale laboratory. The fortuitous sabbatical experiences that put Professors Lederis and Bern on the track of the Urotensins, along with the essential isolation paradigm that resulted in the complete sequencing and synthesis of UI and UII are summarized. The chance interaction between Drs. Vale and Lederis who, prior to the publications of the sequences of UI and CRF, realized the sequence commonalities of these peptides with the vasoactive frog peptide, sauvagine, is outlined. Further, the relationship between the pharmacological studies done with UI in the Calgary laboratory and the more recent understanding of the biology and receptor pharmacology for the entire Urotensin I–CRF–Urocortin peptide family is dealt with. The value of a comparative endocrinology approach to understanding hormone action is emphasized, along with a projection to the future, based on new hypotheses that can be generated by unexplained data already in the literature. Based on the previously described pharmacology of the UI–CRF–Urocortin peptides in a number of target tissues, it is suggested that the use of current molecular approaches can be integrated with a ‘classical’ pharmacological approach to generate new insights about the UI–CRF–Urocortin hormone family.
PMCID: PMC3569504  PMID: 19409389 CAMSID: cams2629
Corticotropin-releasing factor (CRF); CRF1; CRF2; Oxytocin; Urocortin; Urophysis; Urotensin; Vasopressin; Fish; Teleosts
21.  Diagnostic Accuracy of N-Terminal Pro-Brain Natriuretic Peptide in the Evaluation of Postoperative Left Ventricular Diastolic Dysfunction 
Texas Heart Institute Journal  2008;35(2):111-118.
We compared the diagnostic accuracy of N-terminal prohormone brain natriuretic peptide (NT-proBNP) with that of echocardiography in the evaluation of left ventricular diastolic dysfunction after coronary artery bypass grafting.
Thirty patients were studied prospectively. Patients who had recent myocardial infarction, unstable angina pectoris, or low ejection fraction with systolic dysfunction were excluded. Two blood samples were obtained: before anesthetic induction and on the 7th postoperative day. Levels of NT-proBNP were measured by electrochemiluminescence immunoassay. Comprehensive echocardiographic Doppler examinations were performed on admission and on the 7th postoperative day. Relationships between NT-proBNP levels and echocardiographic indices were evaluated by correlation, multiple linear regression, and receiver-operating characteristic curve analysis.
There were significant and correlated worsenings in diastolic stage as determined both by echocardiographic indices and NT-proBNP levels. Early transmitral-to-early diastolic annular velocity ratio (E/Ea) was found to correlate with both NT-proBNP and postoperative diastolic functional stage (r=0.78, P <0.001). Mitral E/Ea was significantly more sensitive than were NT-proBNP levels in predicting diastolic functional stage. The area under the receiver-operating characteristic curve for NT-proBNP was significantly lower than that of mitral E/Ea (mean difference, 0.12; P=0.024). The NT-proBNP had 87.5% sensitivity and 55% specificity, whereas E/Ea had 87.5% sensitivity and 86.4% specificity.
Plasma NT-proBNP levels are significantly related to mitral E/Ea ratio, which is a predictor of diastolic stage. Therefore, elevated NT-proBNP levels may indicate the time for a Doppler echocardiographic evaluation and identify a subgroup of patients at high risk who need closer monitoring during the early postoperative period.
PMCID: PMC2435446  PMID: 18612440
Diastole/physiology; echocardiography; heart ventricles; left ventricular dysfunction; myocardial ischemia/diagnosis; natriuretic peptide, brain/blood/diagnostic use; predictive value of tests; pro-brain natriuretic peptide; sensitivity and specificity; ventricular dysfunction, left/blood/diagnosis/physiology
22.  Potential Clinical Implications of the Urotensin II Receptor Antagonists 
Urotensin II (UII) binds to its receptor, UT, playing an important role in the heart, kidneys, pancreas, adrenal gland, and central nervous system. In the vasculature, it acts as a potent endothelium-independent vasoconstrictor and endothelium-dependent vasodilator. In disease states, however, this constriction–dilation equilibrium is disrupted. There is an upregulation of the UII system in heart disease, metabolic syndrome, and kidney failure. The increase in UII release and UT expression suggest that UII system may be implicated in the pathology and pathogenesis of these diseases by causing an increase in acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) activity leading to smooth muscle cell proliferation and foam cell infiltration, insulin resistance (DMII), as well as inflammation, high blood pressure, and plaque formation. Recently, UT antagonists such as SB-611812, palosuran, and most recently a piperazino-isoindolinone based antagonist have been developed in the hope of better understanding the UII system and treating its associated diseases.
PMCID: PMC3143724  PMID: 21811463
UT; heart; metabolic syndrome; kidney; antagonist
23.  Prognostic value of N-terminal pro-brain natriuretic peptide in elderly people with acute myocardial infarction: prospective observational study 
Objective To examine the influence of age on the predictive value of N-terminal pro-brain natriuretic (NT-proBNP) peptide assay in acute myocardial infarction.
Design Prospective observational study.
Setting All intensive care units in one French region.
Participants 3291 consecutive patients admitted for an acute myocardial infarction, from the RICO survey (a French regional survey for acute myocardial infarction).
Main outcome measure Cardiovascular death at 1 year.
Results Among the 3291 participants, mean age was 68 (SD 14) years and 2356 (72%) were men. In the study population, the median NT-proBNP concentration was 1053 (interquartile range 300-3472) pg/ml. Median values for age quarters 1 to 4 were 367 (119-1050), 696 (201-1950), 1536 (534-4146), and 3774 (1168-9724) pg/ml (P<0.001). A multiple linear regression analysis was done to determine the factors associated with the pro-peptide concentrations in the overall population. NT-proBNP was mainly associated with age, left ventricular ejection fraction, creatinine clearance, female sex, hypertension, diabetes, and anterior wall infarction. At one year’s follow-up, 384 (12%) patients had died from all causes and 372 (11%) from cardiovascular causes. In multivariate analysis, NT-proBNP remained strongly associated with the outcome, beyond traditional risk factors including creatinine clearance and left ventricular ejection fraction, in each age group except in the youngest one (<54 years) (P=0.29). The addition of NT-proBNP significantly improved the performance of the statistical model in the overall study population (−2log likelihood 3179.58 v 3099.74, P<0.001) and in each age quarter including the upper one (1523.52 v 1495.01, P<0.001).The independent discriminative value of NT-proBNP compared with the GRACE score was tested by a diagonal stratification using the median value of the GRACE score and NT-proBNP in older patients (upper quarter). Such stratification strikingly identified a high risk group—patients from the higher NT-proBNP group and with a high risk score—characterised by a risk of death of almost 50% at one year.
Conclusions In this large contemporary non-selected cohort of patients with myocardial infarction, NT-proBNP concentration had incremental prognostic value even in the oldest patients, above and beyond the GRACE risk score and traditional biomarkers after acute myocardial infarction. These data further support the potential interest of clinical trials specifically assessing NT-proBNP measurement as a guide to current treatment strategies, as well as novel strategies, in older patients with acute myocardial infarction.
PMCID: PMC2678205  PMID: 19420032
24.  Complementary Roles for Biomarkers of Biomechanical Strain ST2 and N-Terminal Prohormone B-Type Natriuretic Peptide in Patients With ST-Elevation Myocardial Infarction 
Circulation  2008;117(15):1936-1944.
ST2 is a member of the interleukin-1 receptor family with a soluble form that is markedly upregulated on application of biomechanical strain to cardiac myocytes. Circulating ST2 levels are elevated in the setting of acute myocardial infarction, but the predictive value of ST2 independent of traditional clinical factors and of an established biomarker of biomechanical strain, N-terminal prohormone B-type natriuretic peptide (NT-proBNP), has not been established.
Methods and Results
We measured ST2 at baseline in 1239 patients with ST-elevation myocardial infarction from the CLopidogrel as Adjunctive ReperfusIon TherapY–Thrombolysis in Myocardial Infarction 28 (CLARITY-TIMI 28) trial. Per trial protocol, patients were to undergo coronary angiography after 2 to 8 days and were followed up for 30 days for clinical events. In contrast to NT-proBNP, ST2 levels were independent of clinical factors potentially related to chronic increased left ventricular wall stress, including age, hypertension, prior myocardial infarction, and prior heart failure; levels also were only modestly correlated with NT-proBNP (r=0.14). After adjustment for baseline characteristics and NT-proBNP levels, an ST2 level above the median was associated with a significantly greater risk of cardiovascular death or heart failure (third quartile: adjusted odds ratio, 1.42; 95% confidence interval, 0.68 to 3.57; fourth quartile: adjusted odds ratio, 3.57; 95% confidence interval, 1.87 to 6.81; P<0.0001 for trend). When both ST2 and NT-proBNP were added to a model containing traditional clinical predictors, the c statistic significantly improved from 0.82 (95% confidence interval, 0.77 to 0.87) to 0.86 (95% confidence interval, 0.81 to 0.90) (P=0.017).
In ST-elevation myocardial infarction, high baseline ST2 levels are a significant predictor of cardiovascular death and heart failure independently of baseline characteristics and NT-proBNP, and the combination of ST2 and NT-proBNP significantly improves risk stratification. These data highlight the prognostic value of multiple, complementary biomarkers of biomechanical strain in ST-elevation myocardial infarction.
PMCID: PMC4273564  PMID: 18378613
myocardial infarction; natriuretic peptides; prognosis
25.  Multi-Marker Strategy of Natriuretic Peptide with Either Conventional or High-Sensitivity Troponin-T for Acute Coronary Syndrome Diagnosis in Emergency Department Patients with Chest Pain: From the ROMICAT Trial 
American Heart Journal  2012;163(6):972-979.e1.
Compared to troponin alone, a dual-marker strategy with natriuretic peptides may improve acute coronary syndrome (ACS) diagnosis with a single blood draw and provide physiologic information regarding underlying heart disease. We evaluate the value of adding natriuretic peptides (myocyte stress markers) to troponins (myocardial injury markers) for diagnosing ACS in emergency department (ED) patients with chest pain.
In 328 patients (53 ± 12 years, 63% men) with an initially negative conventional troponin and nonischemic electrocardiogram who underwent 64-slice cardiac computed tomography (CT), we measured conventional troponin-T (cTnT), high-sensitivity troponin-T (hsTnT), N-terminal pro-B type natriuretic peptide (NT-proBNP), and mid-regional pro-atrial natriuretic peptide (MR-proANP). ACS was defined as myocardial infarction or unstable angina. CT was evaluated for coronary plaque, stenosis, and regional wall motion abnormality (RWMA).
Patients with ACS (n=29, 9%) had higher concentrations of each biomarker compared to those without (all p <0.01). Adding natriuretic peptides, especially NT-proBNP, to both cTnT orhsTnT improved the C-statistics and net reclassification index for ACS, largely driven by correctly reclassifying events. Dual-negative marker results improved sensitivity (cTnT 38% to 83–86%, hsTnT 59% to 86–90%; all p <0.01) and negative predictive value (cTnT94% to 97–98%, hsTnT 96% to 97–98%) for ACS. Patients with dual-negative markers had the lowest percentage of CT coronary plaque, stenosis, and RWMA (all p-trend <0.001).
Among ED patients with low-intermediate likelihood of ACS, combining natriuretic peptides with either conventional or highly-sensitive troponin improved discriminatory capacity and allowed for better reclassification of ACS, findings supported by structural and functional CT results.
PMCID: PMC3383806  PMID: 22709749
natriuretic peptides; troponins; acute coronary syndrome; emergency department; computed tomography

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