Urantide: an ultrapotent urotensin II antagonist peptide in the rat aorta

Patacchini, Riccardo; Santicioli, Paolo; Giuliani, Sandro; Grieco, Paolo; Novellino, Ettore; Rovero, Paolo; Maggi, Carlo Alberto

doi:10.1038/sj.bjp.0705555

Cited by 93 publications

(88 citation statements)

References 19 publications

(34 reference statements)

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“…Urantide [Pen5,DTrp7, Orn8]hUII(4 -11) is one of the most potent peptide antagonists to the UT receptor (152), capable of mediating the pathological effects of UII in a variety of diseases. Of relevance to hypertension, in the rat thoracic aorta, urantide antagonizes UII-mediated vasoconstriction (pK B ϭ 8.3), while leaving ET-1 and noradrenaline-induced contraction undisturbed (96). Of relevance to atherosclerosis, urantide antagonizes UII-induced ACAT-1 upregulation (139).…”

Section: Potential Therapeutic Applicationsmentioning

confidence: 99%

Role of urotensin II in health and disease

Ross

McKendy

Giaid

2010

American Journal of Physiology-Regulatory, Integrative and Comp

125

107

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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 2ϩ 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.UT receptor; somatostatin; human; experimental animals; autocrine/paracrine UROTENSIN II (UII) was initially isolated from the urophysis of the goby fish (Gillichthys mirabilis) (97). The peptide was subsequently isolated from the white sucker (Catostomus commersoni) and the carp (Cyprinus carpio). Although there were variations in the amino acid sequence near the amino terminus, in both species the UII molecule retained the COOH-terminal cyclic sequence: -Cys

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Section: Potential Therapeutic Applicationsmentioning

confidence: 99%

Role of urotensin II in health and disease

Ross

McKendy

Giaid

2010

American Journal of Physiology-Regulatory, Integrative and Comp

125

107

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“…Patacchini et al 22 showed that urantide binds with nanomolar affinity (pK i 8.3) to the recombinant hUT and antagonizes (pK B 8.3) the contractile effects of U-II in the rat aorta without showing any residual agonist activity. In our study, urantide dose-dependently inhibited the U-II-induced ACAT-1 upregulation in human monocyte-derived macrophages.…”

Section: Limitationsmentioning

confidence: 99%

“…Anti-U-II antibody (20 L/2 mL plate), 21 urantide (10 nmol/L), 22 the selective UT receptor antagonist peptide, or 4-aminoquinoline (100 nmol/L), 23 the selective UT receptor antagonist nonpeptide, were added 1 hour before the addition of U-II. To evaluate the postreceptor intracellular signal transduction pathways of U-II-induced ACAT-1 expression, GDP-␤-S (100 mol/L), 12 a specific G-protein inactivator, PP2 (1 mol/ L), 12 a specific c-Src protein tyrosine kinase inhibitor, rottlerin (10 mol/L), 24 a specific protein kinase C (PKC) inhibitor, PD98059 (10 mol/L), 11 a specific mitogen-activated protein kinase kinase (MEK) inhibitor, or Y27632 (10 mol/L), 13 a specific Rho kinase (ROCK) inhibitor, were added together with U-II.…”

Section: Cell Culturementioning

confidence: 99%

Human Urotensin II Accelerates Foam Cell Formation in Human Monocyte-Derived Macrophages

et al. 2005

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Abstract-Human urotensin II (U-II), the most potent vasoconstrictor peptide identified to date, and its receptor (UT) are involved in hypertension and atherosclerosis. Acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) converts intracellular free cholesterol into cholesterol ester (CE) for storage in lipid droplets and plays an important role in the formation of macrophage-derived foam cells in atherosclerotic lesions. We examined the effects of U-II on ACAT-1 expression and CE accumulation in human monocyte-derived macrophages. U-II increased ACAT activity in a concentration-dependent manner after 7 days in monocyte primary culture. Immunoblotting analysis showed that U-II at 25 nmol/L increased ACAT-1 protein expression level by 2.5-fold, which was completely abolished by anti-U-II antibody, selective UT receptor antagonists (urantide and 4-aminoquinoline), a G-protein inactivator (GDP-␤-S), a c-Src protein tyrosine kinase inhibitor (PP2), a protein kinase C (PKC) inhibitor (rottlerin), a mitogen-activated protein kinase kinase (MEK) inhibitor (PD98059), or a Rho kinase (ROCK) inhibitor (Y27632). Northern blotting analysis indicated that among the 4 ACAT-1 mRNA transcripts (2.8-, 3.6-, 4.3-, and 7.0-kb), the 2.8-and 3.6-kb transcript levels were selectively upregulated by Ϸ1

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“…The present study [16] investigated the possibility that the previous contradictions related to differences in age or cardiovascular health. The authors investigated healthy men and men with symptomatic vascular disease using a dose ramp and a separate prolonged (60 min) infusion protocol using both U-II and a potent antagonist peptide (urantide) which displaces UII from specific binding to recombinant human UII receptors [17]. They confirmed their earlier negative findings.…”

Section: Pre-translational Researchmentioning

confidence: 55%

Endothelial progenitor cells & translational research

Ritter

2009

Brit J Clinical Pharma

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Urantide: an ultrapotent urotensin II antagonist peptide in the rat aorta

Cited by 93 publications

References 19 publications

Role of urotensin II in health and disease

Role of urotensin II in health and disease

Human Urotensin II Accelerates Foam Cell Formation in Human Monocyte-Derived Macrophages

Endothelial progenitor cells & translational research

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