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 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.

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.

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 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.

EGFR trans-activation by urotensin II receptor is mediated by ß-arrestin recruitment and confers cardioprotection in pressure overload-induced cardiac hypertrophy.

Urotensin II (UTII) and its seven trans-membrane receptor (UTR) are up-regulated in the heart under pathological conditions. Previous in vitro studies have shown that UTII trans-activates the epidermal growth factor receptor (EGFR), however, the role of such novel signalling pathway stimulated by UTII is currently unknown. In this study, we hypothesized that EGFR trans-activation by UTII might exert a protective effect in the overloaded heart. To test this hypothesis, we induced cardiac hypertrophy by transverse aortic constriction (TAC) in wild-type mice, and tested the effects of the UTII antagonist Urantide (UR) on cardiac function, structure, and EGFR trans-activation. After 7 days of pressure overload, UR treatment induced a rapid and significant impairment of cardiac function compared to vehicle. In UR-treated TAC mice, cardiac dysfunction was associated with reduced phosphorylation levels of the EGFR and extracellular-regulated kinase (ERK), increased apoptotic cell death and fibrosis. In vitro UTR stimulation induced membrane translocation of ß-arrestin 1/2, EGFR phosphorylation/internalization, and ERK activation in HEK293 cells. Furthermore, UTII administration lowered apoptotic cell death induced by serum deprivation, as shown by reduced TUNEL/Annexin V staining and caspase 3 activation. Interestingly, UTII-mediated EGFR trans-activation could be prevented by UR treatment or knockdown of ß-arrestin 1/2. Our data show, for the first time in vivo, a new UTR signalling pathway which is mediated by EGFR trans-activation, dependent by ß-arrestin 1/2, promoting cell survival and cardioprotection.

Role of urotensin II in health and disease.

Urotensin II (UII) is an 11 amino acid cyclic peptide originally isolated from the goby fish. The amino acid sequence of UII is exceptionally conserved across most vertebrate taxa, sharing structural similarity to somatostatin. UII binds to a class of G protein-coupled receptor known as GPR14 or the urotensin receptor (UT). UII and its receptor, UT, are widely expressed throughout the cardiovascular, pulmonary, central nervous, renal, and metabolic systems. UII is generally agreed to be the most potent endogenous vasoconstrictor discovered to date. Its physiological mechanisms are similar in some ways to other potent mediators, such as endothelin-1. For example, both compounds elicit a strong vascular smooth muscle-dependent vasoconstriction via Ca(2+) release. UII also exerts a wide range of actions in other systems, such as proliferation of vascular smooth muscle cells, fibroblasts, and cancer cells. It also 1) enhances foam cell formation, chemotaxis of inflammatory cells, and inotropic and hypertrophic effects on heart muscle; 2) inhibits insulin release, modulates glomerular filtration, and release of catecholamines; and 3) may help regulate food intake and the sleep cycle. Elevated plasma levels of UII and increased levels of UII and UT expression have been demonstrated in numerous diseased conditions, including hypertension, atherosclerosis, heart failure, pulmonary hypertension, diabetes, renal failure, and the metabolic syndrome. Indeed, some of these reports suggest that UII is a marker of disease activity. As such, the UT receptor is emerging as a promising target for therapeutic intervention. Here, a concise review is given on the vast physiologic and pathologic roles of UII.

Urotensin-II as an angiogenic factor.

Angiogenesis, the process through which new blood vessels arise from pre-existing ones, is regulated by numerous "classic" factors and other "nonclassic" regulators of angiogenesis. Among these latter urotensin-II is a cyclic 11-amino acid (human) or 15-amino acid (rodent) peptide, originally isolated from the fish urophysis, which exerts a potent systemic vasoconstrictor and hypertensive effect. This review article summarizes the literature data concerning the involvement of urotensin-II in angiogenesis.

Urotensin II induces transactivation of the epidermal growth factor receptor via transient oxidation of SHP-2 in the rat renal tubular cell line NRK-52E.

Urotensin-II (UII) is a potent vasoactive peptide that has been implicated in cardiac fibrosis and renal diseases. However, the role played by UII in renal tissues is largely unknown. In this study, we investigated the effects of human UII (hUII) on rat renal proximal tubular cells of the NRK-52E line and the role of Src homology 2-containing phosphotyrosine phosphatase (SHP-2) in the hUII-induced transactivation of the epidermal growth factor receptor (EGFR). Exposure to hUII at low concentrations significantly induced proliferation in NRK-52E cells; this effect was inhibited by treatment with an ERK1/2 inhibitor (PD98059). UII treatment increased the phosphorylation of EGFR and induced the generation of reactive oxygen species (ROS). Treatment of the ROS scavenger N-acetyl-cysteine (NAC) inhibited EGFR transactivation and ERK phosphorylation induced by hUII. SHP-2 was found to interact with EGFR and be transiently oxidized following the hUII treatment. In SHP-2 knockdown cells, UII-induced phosphorylation of EGFR was less influenced by NAC, and significantly suppressed by heparin binding (HB)-EGF neutralizing antibody. Our data suggest that the ROS-mediated oxidation of SHP-2 is essential for the hUII-induced mitogenic pathway in NRK-52E cells.

Expression and functional role of urotensin-II and its receptor in the adrenal cortex and medulla: novel insights for the pathophysiology of primary aldosteronism.

CONTEXT: The involvement of urotensin II, a vasoactive peptide acting via the G protein-coupled urotensin II receptor, in arterial hypertension remains contentious. OBJECTIVE: We investigated the expression of urotensin II and urotensin II receptor in adrenocortical and adrenomedullary tumors and the functional effects of urotensin II receptor activation. DESIGN: The expression of urotensin II and urotensin II receptor was measured by real time RT-PCR in aldosterone-producing adenoma (n = 22) and pheochromocytoma (n = 10), using histologically normal adrenocortical (n = 6) and normal adrenomedullary (n = 5) tissue as control. Urotensin II peptide and urotensin II receptor protein were investigated with immunohistochemistry and immunoblotting. To identify urotensin II-related and urotensin II receptor-related pathways, a whole transcriptome analysis was used. The adrenocortical effects of urotensin II receptor activation were also assessed by urotensin II infusion with/without the urotensin II receptor antagonist palosuran in rats. RESULTS: Urotensin II was more expressed in pheochromocytoma than in aldosterone-producing adenoma tissue; the opposite was seen for the urotensin II receptor expression. Urotensin II receptor activation in vivo in rats enhanced (by 182 +/- 9%; P < 0.007) the adrenocortical expression of immunoreactive aldosterone synthase. CONCLUSIONS: Urotensin II is a putative mediator of the effects of the adrenal medulla and pheochromocytoma on the adrenocortical zona glomerulosa. This pathophysiological link might account for the reported causal relationship between pheochromocytoma and primary aldosteronism.

Cardiovascular effects of native and non-native urotensin II and urotensin II-related peptide on rat and salmon hearts.

Urotensin II (UII) was first discovered in the urophyses of goby fish and later identified in mammals, while urotensin II-related peptide (URP) was recently isolated from rat brain. We studied the effects of UII on isolated heart preparations of Chinook salmon and Sprague-Dawley rats. Native rat UII caused potent and sustained, dose-dependent dilation of the coronary arteries in the rat, whereas non-native UII (human and trout UII) showed attenuated vasodilation. Rat URP dilated rat coronary arteries, with 10-fold less potency compared with rUII. In salmon, native trout UII caused sustained dilation of the coronary arteries, while rat UII and URP caused significant constriction. Nomega-nitro-(l)-arginine methyl (l-NAME) and indomethacin significantly attenuated the URP and rat UII-induced vasodilation in the rat heart. We conclude that UII is a coronary vasodilator, an action that is species form specific. We also provide the first evidence for cardiac actions of URP, possibly via mechanisms common with UII.

Widespread tissue distribution and diverse functions of corticotropin-releasing factor and related peptides.

Peptides of the corticotropin-releasing factor (CRF) family are expressed throughout the central nervous system (CNS) and in peripheral tissues where they play diverse roles in physiology, behavior, and development. Current data supports the existence of four paralogous genes in vertebrates that encode CRF, urocortin/urotensin 1, urocortin 2 or urocortin 3. Corticotropin-releasing factor is the major hypophysiotropin for adrenocorticotropin, and also functions as a thyrotropin-releasing factor in non-mammalian species. In the CNS, CRF peptides function as neurotransmitters/neuromodulators. Recent work shows that CRF peptides are also expressed at diverse sites outside of the CNS in mammals, and we found widespread expression of CRF and urocortins, CRF receptors and CRF binding protein (CRF-BP) genes in the frog Xenopus laevis. The functions of CRF peptides expressed in the periphery in non-mammalian species are largely unexplored. We recently found that CRF acts as a cytoprotective agent in the X. laevis tadpole tail, and that the CRF-BP can block CRF action and hasten tail muscle cell death. The expression of the CRF-BP is strongly upregulated in the tadpole tail at metamorphic climax where it may neutralize CRF bioactivity, thus promoting tail resorption. Corticotropin-releasing factor and urocortins are also known to be cytoprotective in mammalian cells. Thus, CRF peptides may play diverse roles in physiology and development, and these functions likely arose early in vertebrate evolution.

Exercise urotensin II dynamics in myocardial infarction survivors with and without hypertension.

BACKGROUND: Hypertension is diagnosed in approximately 50% of patients with acute myocardial infarction. Urotensin II (U-II) - a potent vasoactive peptide shown to be elevated in hypertensive subjects, can contribute to negative myocardial remodelling and development of left ventricular failure. Data concerning U-II activity under exercise conditions and its influence on blood pressure in patients after myocardial infarction is scant. Therefore we sought to determine U-II dynamics during exercise in myocardial infarction survivors with and without hypertension. METHODS: Forty patients with acute myocardial infarction treated with successful primary coronary angioplasty, after four weeks of uneventful and symptom-free period following initial hospitalization underwent treadmill exercise test. U-II plasma concentration was measured before and shortly after the exercise. RESULTS: Hypertension was diagnosed in 17 (42.5%) patients. We found no significant differences between normotensive and hypertensive subjects except higher smoking rate and lower calcium channel blockers prescription in normotensive patients. Both systolic and diastolic blood pressure were comparable between study groups before exercise. After exercise we observed higher systolic blood pressure in hypertensive subjects (169.06 +/- 30.23 vs. 150.0 +/- 18.97 mm Hg; p < 0.05). U-II concentration showed no significant difference in pretest sampling (54.93 +/- 38.11 vs. 73.97 +/- 48.52 ng/ml; p = NS). After exercise we noted significantly higher peptide level in hypertensive patients (63.32 +/- 36.11 vs. 98.03 +/- 40.47 ng/ml; p = 0.01). CONCLUSIONS: The present study is the first one to show differences in U-II concentration exercise dynamics in hypertensive and normotensive myocardial infarction survivors. It sheds additional light on hypertension pathophysiology in myocardial infarction patients, and thus identifies a novel, potentially relevant, target for future therapeutic interventions.

Urotensin II: its function in health and its role in disease.

Urotensin II (U-II) is the most potent vasoconstrictor known, even more potent than endothelin-1. It was first isolated from the fish spinal cord and has been recognized as a hormone in the neurosecretory system of teleost fish for over 30 years. After the identification of U-II in humans and the orphan human G-protein-coupled receptor 14 as the urotensin II receptor, UT, many studies have shown that U-II may play an important role in cardiovascular regulation. Human urotensin II (hU-II) is an 11 amino acid cyclic peptide, generated by proteolytic cleavage from a precursor prohormone. It is expressed in the central nervous system as well as other tissues, such as kidney, spleen, small intestine, thymus, prostate, pituitary, and adrenal gland and circulates in human plasma. The plasma U-II level is elevated in renal failure, congestive heart failure, diabetes mellitus, systemic hypertension and portal hypertension caused by liver cirrhosis. The effect of U-II on the vascular system is variable, depending on species, vascular bed and calibre of the vessel. The net effect on vascular tone is a balance between endothelium-independent vasoconstriction and endothelium-dependent vasodilatation. U-II is also a neuropeptide and may play a role in tumour development. The development of UT receptor antagonists may provide a useful research tool as well as a novel treatment for cardiorenal diseases.

Urotensin II: ancient hormone with new functions in vertebrate body fluid regulation.

Urotensin II (UII), described in many fish species, is secreted by the caudal neurosecretory system, a unique fish neuroendocrine structure. We have examined UII secretion and its control in euryhaline fish, supporting a proposed role in osmoregulation. However, it is now apparent that UII is present in other vertebrates, including mammals. The 12-amino-acid peptide has been highly conserved and the key cyclic region is common from fish to humans. Our UII radioimmunoassay for flounder, directed to this cyclic region, has shown circulating UII levels in humans and rats comparable with those in fish. In mammals, UII cardiovascular effects vary between species, with vasoconstriction only evident in specific vascular beds. The kidney expresses UII receptors and responds to UII administration by a reduction in glomerular filtration rate, urine flow, and excretion of the major ions. Interestingly, plasma levels of UII are chronically elevated in rat models of hypertension. These observations imply an unforeseen role for this ancient fish hormone in the physiological and perhaps pathophysiological regulation of body fluids in higher vertebrates, including humans.

Urotensin II and cardiovascular diseases.

Urotensin II (UII) has been found to be a potent vasoactive peptide in humans and in a number of relevant animal models of cardiovascular disease such as the mouse, rat and other non-human primates. This peptide with structural homology to somatostatin was first isolated from the urophysis of fish and was recently found to bind to an orphan receptor in mouse and human. Initially found to have potent vasoconstrictive activities in a variety of vessels from diverse species, it has also been shown to exert vasodilatation in certain vessels in the rat and human by various endothelium-dependent mechanisms. The various vasoactive properties of UII suggest that the peptide may have a physiological role in maintaining vascular tone and therefore may have a role in the pathophysiology of a number of human diseases such as heart failure. Moreover, UII has also been implicated as a mitogen of vascular smooth muscle cells suggesting a deleterious role in atherosclerosis and coronary artery disease. In addition, there is evidence to demonstrate that UII has multiple metabolic effects on cholesterol metabolism, glycemic control and hypertension and therefore may be implicated in the development of insulin resistance and the metabolic syndrome.