Urotensin 2 in Kawasaki disease pathogenesis.

BackgroundGenetic variation in calcium signaling pathways is associated with Kawasaki disease (KD) susceptibility and coronary artery aneurysms (CAA). Expression quantitative trait locus analysis for KD-associated variants in calcium/sodium channel gene solute carrier family 8 member 1 (SLC8A1) revealed an effect on expression of urotensin 2 (UTS2). We speculated that UTS2 is influenced by genetic variation in SLC8A1 and contributes to disease pathogenesis.MethodsWe measured levels of UTS2 and its receptor in blood and tissues using quantitative reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemical staining.ResultsUTS2 transcript levels were higher in the whole blood of subjects with KD homozygous for three risk alleles in SLC8A1 (P=0.002-0.006). Increased levels of plasma UTS2 varied as a function of SLC8A1 genotype (P=0.008-0.04). UTS2 and UTS2 receptor were expressed in mononuclear inflammatory cells and spindle-shaped cells in the coronary arterial wall of a patient suffering from KD with CAA and in a femoral endarterectomy specimen from an adult patient with peripheral aneurysms following KD in childhood.ConclusionHost genetics influences UTS2 levels, which may contribute to inflammation and cardiovascular damage in KD.

[Research progress of urotensin â ¡ and urotensin â ¡ receptor].

Urotensin II (UII) is the most potent vasoconstrictor among the identified vasoactive peptides. UII and its receptor (UT), which play varies of physiological roles, are widely expressed in central nerve system and peripheral organs. The change on the expressional level of UII/UT system has been proved to be closely correlated with pathological conditions. Therefore, UII/UT system was considered to be a potential target for treating many diseases. This review article is devoted to the latest research progress of UII/UT system in several aspects including ligand and receptor distribution, physiological activity, characteristics under pathological conditions and antagonist classification.

Urotensin II contributes to collagen synthesis and up-regulates Egr-1 expression in cultured pulmonary arterial smooth muscle cells through the ERK1/2 pathway.

AIM: The objective of this study was to investigate the effects of urotensin II (UII) treatment on the proliferation and collagen synthesis of cultured rat pulmonary arterial smooth muscle cells (PASMCs) and to explore whether these effects are mediated by mitogen-activated protein kinase (MAPK) signaling pathways and early growth response 1 (Egr-1). METHODS: The proliferation of cultured PASMCs stimulated with different doses of UII was detected by BrdU incorporation. The mRNA expression levels of procollagen I (procol I), procollagen III (procol III), extracellular regulated protein kinase 1/2 (ERK1/2), stress-stimulated protein kinase (Sapk), p38 MAPK (p38), and Egr-1 mRNA in cultured PASMCs after treatment with UII, the UII-specific antagonist urantide, and the ERK1/2 inhibitor PD98059 were detected by real-time polymerase chain reaction (PCR), and the protein expression levels of procol I, procol III, phosphorylated (p)-ERK1/2, p-Sapk, p-p38, and Egr-1 were detected by Western blotting. RESULTS: Treatment with UII increased the proliferation of cultured PASMCs in a dose-dependent manner (P<0.05). However, treatment with urantide and PD98059 inhibited the promoting effect of UII on PASMC proliferation (P<0.05). Real-time PCR analysis showed that UII up-regulated the expression of procol I, procol III, ERK1/2, Sapk, and Egr-1 mRNA (P<0.05), but not p38 mRNA. However, the up-regulating effect of UII was inhibited by PD98059 and urantide. Western blotting analysis showed that UII increased the synthesis of collagen I, collagen III, p-ERK1/2, p-Sapk, and Egr-1, and these effects also were inhibited by PD98059 and urantide (P<0.05). CONCLUSIONS: Egr-1 participates in the UII-mediated proliferation and collagen synthesis of cultured rat PASMCs via activation of the ERK1/2 signaling pathway.

Urotensin-II receptor stimulation of cardiac L-type Ca2+ channels requires the ßγ subunits of Gi/o-protein and phosphatidylinositol 3-kinase-dependent protein kinase C ß1 isoform.

Recent studies have demonstrated that urotensin-II (U-II) plays important roles in cardiovascular actions including cardiac positive inotropic effects and increasing cardiac output. However, the mechanisms underlying these effects of U-II in cardiomyocytes still remain unknown. We show by electrophysiological studies that U-II dose-dependently potentiates L-type Ca(2+) currents (ICa,L) in adult rat ventricular myocytes. This effect was U-II receptor (U-IIR)-dependent and was associated with a depolarizing shift in the voltage dependence of inactivation. Intracellular application of guanosine-5'-O-(2-thiodiphosphate) and pertussis toxin pretreatment both abolished the stimulatory effects of U-II. Dialysis of cells with the QEHA peptide, but not scrambled peptide SKEE, blocked the U-II-induced response. The phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin as well as the class I PI3K antagonist CH132799 blocked the U-II-induced ICa,L response. Protein kinase C antagonists calphostin C and chelerythrine chloride as well as dialysis of cells with 1,2bis(2aminophenoxy)ethaneN,N,N',N'-tetraacetic acid abolished the U-II-induced responses, whereas PKCα inhibition or PKA blockade had no effect. Exposure of ventricular myocytes to U-II markedly increased membrane PKCß1 expression, whereas inhibition of PKCß1 pharmacologically or by shRNA targeting abolished the U-II-induced ICa,L response. Functionally, we observed a significant increase in the amplitude of sarcomere shortening induced by U-II; blockade of U-IIR as well as PKCß inhibition abolished this effect, whereas Bay K8644 mimicked the U-II response. Taken together, our results indicate that U-II potentiates ICa,L through the ßγ subunits of Gi/o-protein and downstream activation of the class I PI3K-dependent PKCß1 isoform. This occurred via the activation of U-IIR and contributes to the positive inotropic effect on cardiomyocytes.

Urotensin II inhibits doxorubicin-induced human umbilical vein endothelial cell death by modulating ATF expression and via the ERK and Akt pathway.

BACKGROUND AND PURPOSE: Regulation of the homeostasis of vascular endothelium is critical for the processes of vascular remodeling and angiogenesis under physiological and pathological conditions. Urotensin II (U-II), a potent vasoactive peptide, participates in vascular and myocardial remodeling after injury. We investigated the protective effect of U-II on doxorubicin (DOX)-induced apoptosis in cultured human umbilical vein endothelial cells (HUVECs) and the potential mechanisms involved in this process. EXPERIMENTAL APPROACH: Cultured HUVECs were treated with vehicle, DOX (1 µM), U-II, or U-II plus DOX. Apoptosis was evaluated by DNA strand break level with TdT-mediated dUTP nick-end labeling (TUNEL) staining. Western blot analysis was employed to determine the related protein expression and flow cytometry assay was used to determine the TUNEL positive cells. KEY RESULTS: U-II reduced the quantity of cleaved caspase-3 and cytosol cytochrome c and increased Bcl-2 expression, which results in protecting HUVECs from DOX-induced apoptosis. U-II induced Activating transcription factor 3 (ATF3) at both mRNA and protein levels in U-II-treated cells. Knockdown of ATF3 with ATF3 siRNA significantly reduced ATF3 protein levels and U-II protective effect under DOX-treated condition. U-II downregulated p53 expression in DOX-induced HUVECs apoptosis, and it rapidly activated extracellular signal-regulated protein kinase (ERK) and Akt. The DOX induced change of p53 was not affected by U-II antagonist (urantide) under ATF-3 knockdown. The inhibitory effect of U-II on DOX-increased apoptosis was attenuated by inhibitors of ERK (U0126) and PI3K/Akt (LY294002). CONCLUSION AND IMPLICATIONS: Our observations provide evidence that U-II protects HUVECs from DOX-induced apoptosis. ERK-Akt phosphorylation, ATF3 activation, and p53 downregulation may play a signal-transduction role in this process.

Urotensin II receptor determines prognosis of bladder cancer regulating cell motility/invasion.

BACKGROUND: Non Muscle Invasive Bladder Transitional Cancer (NMIBC) and Muscle Invasive Bladder Transitional Cancer (MIBC)/invasive have different gene profile and clinical course. NMIBC prognosis is not completely predictable, since the relapse rate is higher than 20%, even in the form of MIBC. The aim of this study is to evaluate if UTR expression can discriminate between NMIBC and MIBC and predict the risk of relapses in NMIBCs. METHODS: We have investigated upon urotensin-II (UII) receptor (UTR) expression in vivo in 159 patients affected by NMIBC. The biological role of UTR was also investigated in vitro. UTR expression was evaluated in a tissue-micro-array, consisting of normal, NMIBC and invasive bTCC samples. RESULTS: UTR discriminated between NMIBC and MIBC and showed a significant correlation between low UTR expression and shorter disease free survival in NMIBC. The superagonist UPG84 induced growth suppression at nM concentrations on 3/4 cell lines. Bladder cancer cell treatment with the antagonist urantide or the knock-down of UTR with a specific shRNA significantly blocked both the motility and invasion of bladder cancer cells. CONCLUSIONS: The evaluation of UTR expression can discriminate between NMIBC at high and low risk of relapse. Moreover, our data suggest that UTR is involved in the regulation of motility, invasion and proliferation of bladder cancer cells. High UTR expression is an independent prognostic factor of good prognosis for NMIBC regulating motility and invasion of bladder cancer cells.

Urotensin II promotes atherosclerosis in cholesterol-fed rabbits.

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.

Urotensin II induces interleukin 8 expression in human umbilical vein endothelial cells.

BACKGROUND: Urotensin II (U-II), an 11-amino acid peptide, exerts a wide range of actions in cardiovascular systems. Interleukin-8 (IL-8) is secreted by endothelial cells, thereby enhancing endothelial cell survival, proliferation, and angiogenesis. However, the interrelationship between U-II and IL-8 as well as the detailed intracellular mechanism of U-II in vascular endothelial cells remain unclear. The aim of this study was to investigate the effect of U-II on IL-8 expression and to explore its intracellular mechanism in human umbilical vein endothelial cells. METHODS/PRINCIPAL FINDINGS: Primary human umbilical vein endothelial cells were used. Expression of IL-8 was determined by real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and luciferase reporter assay. Western blot analyses and experiments with specific inhibitors were performed to reveal the downstream signaling pathways as concerned. U-II increased the mRNA/protein levels of IL-8 in human umbilical vein endothelial cells. The U-II effects were significantly inhibited by its receptor antagonist [Orn(5)]-URP. Western blot analyses and experiments with specific inhibitors indicated the involvement of phosphorylation of p38 mitogen-activated protein kinase and extracellular signal-regulated kinase in U-II-induced IL-8 expression. Luciferase reporter assay further revealed that U-II induces the transcriptional activity of IL-8. The site-directed mutagenesis indicated that the mutation of AP-1 and NF-kB binding sites reduced U-II-increased IL-8 promoter activities. Proliferation of human umbilical vein endothelial cells induced by U-II could be inhibited significantly by IL-8 RNA interference. CONCLUSION/SIGNIFICANCE: The results show that U-II induces IL-8 expression in human umbilical vein endothelial cells via p38 mitogen-activated protein kinase and extracellular signal-regulated kinase signaling pathways and IL-8 is involved in the U-II-induced proliferation of human umbilical vein endothelial cells.

Urotensin II promotes vagal-mediated bradycardia by activating cardiac-projecting parasympathetic neurons of nucleus ambiguus.

Urotensin II (U-II) is a cyclic undecapeptide that regulates cardiovascular function at central and peripheral sites. The functional role of U-II nucleus ambiguus, a key site controlling cardiac tone, has not been established, despite the identification of U-II and its receptor at this level. We report here that U-II produces an increase in cytosolic Ca(2+) concentration in retrogradely labeled cardiac vagal neurons of nucleus ambiguus via two pathways: (i) Ca(2+) release from the endoplasmic reticulum via inositol 1,4,5-trisphosphate receptor; and (ii) Ca(2+) influx through P/Q-type Ca(2+) channels. In addition, U-II depolarizes cultured cardiac parasympathetic neurons. Microinjection of increasing concentrations of U-II into nucleus ambiguus elicits dose-dependent bradycardia in conscious rats, indicating the in vivo activation of the cholinergic pathway controlling the heart rate. Both the in vitro and in vivo effects were abolished by the urotensin receptor antagonist, urantide. Our findings suggest that, in addition, to the previously reported increase in sympathetic outflow, U-II activates cardiac vagal neurons of nucleus ambiguus, which may contribute to cardioprotection.

Treatment of erectile dysfunction: new targets and strategies from recent research.

In recent years, research on penile erection has increasingly been centered on the molecular mechanisms involved. Major progress has been made in the field and at present a whole number of neurotransmitters, chemical effectors, growth factors, second-messenger molecules, ions, intercellular proteins, and hormones have been characterized as components of the complex process of erection. This knowledge has led to the discovery of several new therapeutic targets and multiple medical approaches for the treatment of erectile dysfunction (ED). This review focuses on the progress made in this field within the last few years.

Contractile responses to rat urotensin II in resting and depolarized basilar arteries.

The effects of human urotensin II (hUII) on the vascular tone of different animal species has been studied extensively. However, little has been reported on the vasoactive effects of rat urotensin (rUII) in murine models. The aim of the present study was to investigate the effects of rUII on vasoreactivity in rat basilar arteries. Basilar arteries from adult male Wistar rats (300-350 g) were isolated, cut in rings, and mounted on a small vessel myograph to measure isometric tension. rUII concentrations were studied in both resting and depolarized state. To remove endothelial nitric oxide effects from the rUII response, we treated selected arterial rings with Nω-nitro-L-arginine methyl ester (L-NAME). 10 µM rUII produced a potent vasoconstrictor response in rat basilar arteries with intact endothelium, while isometric forces remained unaffected in arterial rings treated with lower rUII concentrations. Although L-NAME did not have a significant effect on 10 µM rUII-evoked contraction, it slightly increased arterial ring contraction elicited by 1 µM rUII. In depolarized arteries, dose-dependent rUII increased depolarization-induced contractions. This effect was suppressed by L-NAME. Our results show that the rat basilar artery has a vasoconstrictor response to rUII. The most potent vasoconstrictor effect was produced by lower doses of rUII (0.1 and 1 µM) in depolarized arteries with intact endothelium. This effect could facilitate arterial vasospasm in vascular pathophysiological processes such as subarachnoid hemorrhage and hypertension, when sustained depolarization and L-type Ca(2+) channel activation are present.

The urotensin system is up-regulated in the pre-hypertensive spontaneously hypertensive rat.

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.

Urotensin II exerts antiapoptotic effect on NRK-52E cells through prostacyclin-mediated peroxisome proliferator-activated receptor alpha and Akt activation.

Urotensin II (UII) is a cyclic vasoactive peptide which is mainly expressed in kidneys. Although elevated plasma UII levels are associated with renal impairment, the influence of UII on renal injury is unclear. In this study, we monitored the influence of UII on gentamicin-induced apoptosis in rat tubular cells (NRK-52E). We found that UII significantly reduced gentamicin-induced apoptosis and apoptotic signals. Blocking endogenous UII secretion caused cells to be more susceptible to gentamicin. In gentamicin-treated mice, UII also expressed protective effect on renal tubular cells. UII was also found to induce prostacyclin (PGI2) production, which caused peroxisomal proliferator-activated receptor α (PPARα) activation as revealed by both PGI2 synthase siRNA transfection and piroxicam treatment. Blockage of PPARα by siRNA transfection inhibited UII-induced Akt phosphorylation and the antiapoptotic effect of UII. Our results suggest that UII can protect renal tubular cells from gentamicin-induced apoptosis through PGI2-mediated PPARα and Akt activation.

[Urotensin II--a newly discovered modulator of cardiovascular functions in vertebrates]. / Urotenzín II--novo objavený modulátor kardiovaskulárnych funkcií u stavovcov.

Peptide urotensin II was originally isolated from the urophysis of teleost fishes; later it was identified also in higher vertebrates in various organs and tissues, including cardiovascular structures. Since its discovery it has been considered as a highly potent vasoconstrictor inducing contraction of smooth muscle in subnanomolar concentrations. Its wide distribution as well as its high interspecies homology indicates that this peptide is involved in regulation of many important physiological functions in vertebrates. An effort to discover other possible functions of urotensin II was intensified by the identification of its G-protein coupled receptor and its identification in humans. Furthermore, altered levels of expression of urotensin II and its receptor were found in various disease states including hypertension, diabetes, heart and renal failure, in experimental animal models as well as in humans. Therefore, there is widely discussed question regarding the possible role of urotensin II in etiopathogeneses of these diseases, however the exact mechanisms are still unknown. The aim of this review is to summarize the current knowledge about urotensin II with emphasis to its direct and undirect effects in cardiovascular system.

Urotensin II-induced collagen synthesis in cultured smooth muscle cells from rat aortic media and a possible involvement of transforming growth factor-ß1/Smad2/3 signaling pathway.

BACKGROUND: Recent studies suggest that urotensin II (UII) and transforming growth factor-ß1 (TGF-ß1) both have critical roles in vascular remodeling. UII is a recently discovered vasoconstrictive peptide that is involved in the pathogenesis of atherosclerosis, restenosis and hypertension. TGF-ß1 is an important factor that has a pivotal role in vascular fibrosis. This study aimed to explore whether TGF-ß1 is involved in UII-induced collagen synthesis in rat aortic vascular smooth muscle cells (VSMCs) and examined the effects and mechanisms of UII on collagen synthesis and secretion in VSMCs. METHODS: VSMCs were prepared by the explant culture method. TGF-ß1 and collagen I secretions from the cells were determined by enzyme-linked immunosorbent assay (ELISA). The mRNA and protein expressions of TGF-ß1, collagen I, Smad2 and Smad3 were determined using Real-time RT-PCR and Western blotting. RESULTS: UII dose-dependently promoted TGF-ß1 protein expression and secretion from VSMCs, with maximal effect at 10(-8) mol/l at 24 h for protein expression and 10(-7) mol/l at 24 h for protein secretion (both P<0.01). Moreover, UII dose-dependently promoted Smad2 and Smad3 mRNA expression in VSMCs, with maximal effect at 10(-8) mol/l for 12 h (both P<0.01). The effects of UII were significantly inhibited by its receptor antagonists urantide (10(-6) mol/l) or SB-710411 (10(-6) mol/l), and by the mitogen-activated protein kinase (MAPK/ERK) inhibitor PD98059 (10(-6) mol/l). UII dose-dependently promoted collagen I mRNA expression and protein secretion in VSMCs, with maximal effect at 10(-8) mol/l at 12h for mRNA expression and 10(-6) mol/l at 24 h for protein secretion (both P<0.01). Collagen synthesis and secretion from VSMCs induced by UII were inhibited significantly by a TGF-ß1-specific neutralizing antibody, SB-431542 (an antagonist of the TGF-ß1 type II receptor) and PD98059 (all P<0.01). CONCLUSIONS: This study suggests that UII could induce collagen synthesis and secretion through upregulation of TGF-ß1 expression and secretion in VSMCs, and that TGF-ß1/Smad2/3 signaling might be one of the important pathways by which UII is involved in vascular fibrosis.

Serum urotensin II levels in patients with non-dipper hypertension.

Hypertension terms "dipper" and "non-dipper" are propounded by the change that occurs during ambulatory blood pressure (BP) monitoring. The purpose of this study is to present whether the serum urotensin II levels are different in patients with dipper and non-dipper hypertension and to put forward the effects causing this difference, if there are any. Patients recently diagnosed with hypertension were included in the study. With ambulatory BP monitoring, 81 patients with high BP were divided into two groups, dipper (n = 40) and non-dipper (n = 41). Serum urotensin II levels were analyzed by ELISA method. Serum urotensin II levels were higher in patients with non-dipper hypertension than in patients with dipper hypertension (204 [106-533] vs. 140 [96-309], P = .004). There was a positive correlation between total systolic BP and serum urotensin II levels (r = 0.408 and P = .009), but the relation in the non-dipper hypertension group was not significant (r = 0.194 and P = .2). In conclusion, serum urotensin II levels were higher in non-dipper HT patients than dipper HT patients. This higher urotensin II level might be responsible for poor prognoses.

Urotensin-II system in genetic control of blood pressure and renal function.

Urotensin-II controls ion/water homeostasis in fish and vascular tone in rodents. We hypothesised that common genetic variants in urotensin-II pathway genes are associated with human blood pressure or renal function. We performed family-based analysis of association between blood pressure, glomerular filtration and genes of the urotensin-II pathway (urotensin-II, urotensin-II related peptide, urotensin-II receptor) saturated with 28 tagging single nucleotide polymorphisms in 2024 individuals from 520 families; followed by an independent replication in 420 families and 7545 unrelated subjects. The expression studies of the urotensin-II pathway were carried out in 97 human kidneys. Phylogenetic evolutionary analysis was conducted in 17 vertebrate species. One single nucleotide polymorphism (rs531485 in urotensin-II gene) was associated with adjusted estimated glomerular filtration rate in the discovery cohort (p = 0.0005). It showed no association with estimated glomerular filtration rate in the combined replication resource of 8724 subjects from 6 populations. Expression of urotensin-II and its receptor showed strong linear correlation (r = 0.86, p<0.0001). There was no difference in renal expression of urotensin-II system between hypertensive and normotensive subjects. Evolutionary analysis revealed accumulation of mutations in urotensin-II since the divergence of primates and weaker conservation of urotensin-II receptor in primates than in lower vertebrates. Our data suggest that urotensin-II system genes are unlikely to play a major role in genetic control of human blood pressure or renal function. The signatures of evolutionary forces acting on urotensin-II system indicate that it may have evolved towards loss of function since the divergence of primates.

Urotensin II in invertebrates: from structure to function in Aplysia californica.

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.

Genetic and pharmacological manipulation of urotensin II ameliorate the metabolic and atherosclerosis sequalae in mice.

OBJECTIVE: Urotensin II (UII) is a potent vasoactive peptide that binds to the urotensin receptor-coupled receptor-14 (known as UT) and exerts a wide range of actions in humans and experimental animals. We tested the hypothesis that UII gene deletion or UT blockade ameliorate experimental atherosclerosis. METHODS AND RESULTS: We observed a significant reduction in weight gain, visceral fat, blood pressure, circulating plasma lipids, and proatherogenic cytokines and improvement of glucose tolerance in UII knockout mice compared with wild type (P<0.05). Deletion of UII after an apolipoprotein E knockout resulted in a significant reduction in serum cytokines, adipokines, and aortic atherosclerosis compared with apolipoprotein E knockout mice. Similarly, treatment of apolipoprotein E knockout mice fed on high-fat diet with the UT antagonist SB657510A reduced weight gain, visceral fat, and hyperlipidemia and improved glucose tolerance (P<0.05) and attenuated the initiation and progression of atherosclerosis. The UT antagonist also decreased aortic extracellular signal-regulated kinase 1/2 phosphorylation and oxidant formation and serum level of cytokines (P<0.05). CONCLUSIONS: These findings demonstrate for the first time the role of UII gene deletion in atherosclerosis and suggest that the use of pharmaceutical agents aimed at blocking the UII pathway may provide a novel approach in the treatment of atherosclerosis and its associated precursors such as obesity, hyperlipidemia, diabetes mellitus, and hypertension.

Roles of human urotensin II in volume resistance hypertension in peritoneal dialysis patients.

Human urotensin II (hUII) is a newly discovered substance that can dilate small blood vessels to decrease the blood pressure (BP). Our previous studies showed that some volume-overloaded patients on peritoneal dialysis can maintain normal BP (congestive heart failure excluded), suggesting that these patients have volume resistance capacity. This study is to investigate whether hUII plays an important role in this subgroup of patients on peritoneal dialysis. In this study, 105 patients on continuous ambulatory peritoneal dialysis were enrolled. Volume load was evaluated by the overhydration (OH) value obtained by bioimpedance analysis. OH < 2.0 kg was defined as normal volume (NV), and OH ≥ 2.0 kg as high volume (HV). Systolic blood pressure (SBP) <130 mmHg was defined as normotension (NT) and ≥130 mmHg as hypertension (HT). The patients were thus divided into four subgroups: (1) normotension with normal volume (NT-NV), (2) normotension with high volume (NT-HV), (3) normal volume with hypertension (HT-NV), and (4) high volume with hypertension (HT-HV). hUII was measured using radioimmunoassay method. hUII was significantly higher in normal SBP group than that in high SBP group (p < 0.05). hUII was higher in the NT-HV group compared with that in the HT-HV group (p < 0.05). Our study suggests that hUII may be involved in the pathogenesis of the volume resistance HT in peritoneal dialysis patients.