Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human urotensin-II (hU-II) is the most potent endogenous cardiostimulant identified to date. We therefore determined whether hU-II has a possible pathological role by investigating its levels in patients with congestive heart failure (CHF). Blood samples were obtained from the aortic root, femoral artery, femoral vein, and pulmonary artery from CHF patients undergoing cardiac catheterization and the aortic root from patients undergoing investigative angiography for chest pain who were not in heart failure. Immunoreactive hU-II (hU-II-ir) levels were determined with radioimmunoassay. hU-II-ir was elevated in the aortic root of CHF patients (230.9 +/- 68.7 pg/ml, n = 21; P < 0.001) vs. patients with nonfailing hearts (22.7 +/- 6.1 pg/ml, n = 18). This increase was attributed to cardiopulmonary production of hU-II-ir because levels were lower in the pulmonary artery (38.2 +/- 6.1 pg/ml, n = 21; P < 0.001) than in the aortic root. hU-II-ir was elevated in the aortic root of CHF patients with nonischemic cardiomyopathy (142.1 +/- 51.5 pg/ml, n = 10; P < 0.05) vs. patients with nonfailing hearts without coronary artery disease (27.3 +/- 12.4 pg/ml, n = 7) and CHF patients with ischemic cardiomyopathy (311.6 +/- 120.4 pg/ml, n = 11; P < 0.001) vs. patients with nonfailing hearts and coronary artery disease (19.8 +/- 6.6 pg/ml, n = 11). hU-II-ir was significantly higher in the aortic root than in the pulmonary artery and femoral vein, with a nonsignificant trend for higher levels in the aortic root than in the femoral artery. The findings indicated that hU-II-ir is elevated in the aortic root of CHF patients and that hU-II-ir is cleared at least in part from the microcirculation.
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PMID:Elevated plasma levels of human urotensin-II immunoreactivity in congestive heart failure. 1279 92

Recent studies have revealed the importance of fish-derived peptide hormones to human endocrinology. These peptides include melanin-concentrating hormone (MCH), urocortins (human urotensin-I), and urotensin-II. MCH, a hypothalamic peptide, is a potent stimulator on appetite. Urocortins, e.g. urocortin 1 and urocortin 3 (stresscopin), are endogenous ligands for the corticotropin-releasing factor (CRF) receptors, particularly CRF type 2 receptor, that mediates a vasodilator action, a positive inotropic action and a central appetite-inhibiting action. These actions mediated by CRF type 2 receptor may ameliorate the stress response. Human urotensin-II is a potent vasoconstrictor peptide, while it acts as a vasodilator on some arteries. Human urotensin-II is expressed in various types of cells and tissues, including cardiovascular tissues, as well as many types of tumor cells. Thus, these fish-derived peptides appear to play important roles in human physiology, such as appetite regulation, stress response and cardiovascular regulation, and also in diseases, for example, obesity, cardiovascular diseases and tumors. Development of antagonists/agonists against the receptors for these peptides may open new strategies for the treatment of various diseases, including obesity-related diseases, hypertension, heart failure and malignant tumors.
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PMID:Translational medicine in fish-derived peptides: from fish endocrinology to human physiology and diseases. 1500 3

The pronounced pharmacodynamic effects of human urotensin-II (U-II), a 'somatostatin-like' cyclic undecapeptide, are mediated via the G protein-coupled receptor UT (formerly known as GPR14). Emerging clinical studies implicate U-II in the etiology of several cardiorenal and metabolic disease states in humans. Although the specific pathogenic role(s) of U-II remain to be clearly defined, existing data warrant further clinical investigation. The therapeutic development of specific U-II/UT inhibitors will assist in establishing a causative role for U-II in the progression and/or maintenance of hypertension, heart failure, renal tubular disease and diabetes.
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PMID:Urotensin-II as a novel therapeutic target in the clinical management of cardiorenal disease. 1508 93

The identification of a human homolog of urotensin-II (U-II) and a novel, specific G-protein-coupled receptor by Ames et al. in 1999 changed the perception that the U-II isopeptide family was an esoteric collection of 'somatostatin-like neuropeptides' present only in the nervous systems of an eclectic array of aquatic invertebrates, fish and amphibians. In this article, we review recent developments in the pharmacology of human U-II, focusing on the actions of this peptide in the mammalian cardiorenal system. The putative role of U-II in the etiology of hypertension, heart failure, renal dysfunction and diabetes is discussed, as are novel U-II receptor antagonists.
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PMID:From 'gills to pills': urotensin-II as a regulator of mammalian cardiorenal function. 1510 93

Urotensin-II (U-II) potently contracts some large isolated blood vessels and cardiac tissue. However, the maximum effects on human blood vessels and heart are relatively small. U-II dilates human resistance arteries. It markedly decreased myocardial function and increased vascular resistance in cynomolgus monkeys, but the major effects of U-II have not been observed in healthy humans. A major role for U-II in human cardiovascular disease has not been clearly established despite studies in patients with coronary artery disease, heart failure, essential hypertension and diabetes. Peptide and non-peptide agonists and antagonists of the U-II receptor are being developed and will be useful in the characterisation of the effects of U-II, and may have some therapeutic potential.
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PMID:Urotensin-II and the cardiovascular system--the importance of developing modulators. 1515 23

We detected urotensin-II-like immunoreactivity in the endothelium of normal human blood vessels from heart, kidney, placenta, adrenal, thyroid and umbilical cord. Immunoreactivity was also detected in endocardial endothelial and kidney epithelial cells. In atherosclerotic coronary artery, immunoreactivity localized to regions of macrophage infiltration. Urotensin-II constricted human atherosclerotic epicardial coronary arteries with pD2=10.58 +/- 0.46 (mean +/- S.E.M.) and Emax=11.4 +/- 4.2% KCl and small coronary arteries with pD2=9.25 +/- 0.38 and Emax=77 +/- 16% KCl. Small coronary arteries clearly exhibited a greater maximum response to urotensin-II than epicardial vessels. This enhanced responsiveness may be of importance in heart failure, where circulating concentrations of U-II are increased, or in atherosclerosis where focally up-regulated urotensin-II production may act down stream to produce significant vasospasm, compromising blood flow to the myocardium. We conclude that urotensin-II is a locally released vasoactive mediator that may be an important regulator of blood flow particularly to the myocardium and may have a specific role in human atherosclerosis.
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PMID:Cellular distribution of immunoreactive urotensin-II in human tissues with evidence of increased expression in atherosclerosis and a greater constrictor response of small compared to large coronary arteries. 1547 44

Urotensin-II (U-II), the most potent mammalian vasoconstrictor identified, and its receptor, UT, exhibits increased expression in cardiac tissue and plasma in congestive heart failure (CHF) patients. Cardiomyocyte hypertrophy is primarily responsible for increased myocardial mass associated with cardiac injury. Neurohumoral factors such as angiotensin-II, endothelin-1, catecholamines, and inflammatory cytokines are thought to mediate this response. U-II shares similar biological activities with other hypertrophic G(q)-coupled receptor ligands such as angiotensin-II and endothelin-1, but a role for U-II in cardiomyocyte hypertrophy has not been characterized. The hypothesis of the current study was that U-II, acting through its G(q)-coupled receptor UT plays a hypertrophic role in cardiac hypertrophic remodeling. We report that adenoviral upregulation of the UT receptor "unmasked" U-II-induced hypertrophy in H9c2 cardiomyocytes, with a threshold response of 202+/-8 binding sites/cell. U-II was equally as efficacious as phenylephrine in inducing hypertrophy, measured by a reporter assay (EC(50) 0.7+/-0.2 nM) and [(3)H]-leucine incorporation (EC(50) 150+/-40 nM). A competitive peptidic UT receptor antagonist, BIM-23127, inhibited U-II-induced hypertrophy ( K(B) 34+/-6 nM). U-II did not affect cell proliferation or apoptosis, indicating that U-II is more hypertrophic than apoptotic or hyperplastic in cardiomyocytes. U-II (10 nM) stimulated interleukin-6 release in UT-expressing cardiomyocytes (4.6-fold at 6 h). Finally, in a rat heart failure model, cardiac ventricular mRNA expression of U-II, UT receptor, interleukin-6, and interleukin-1-beta is increased time-dependently following myocardial injury. These results indicate that U-II might play a role in cardiac remodeling associated with CHF by stimulation of cardiomyocyte hypertrophy via UT, and through upregulation of inflammatory cytokines. As such, UT antagonism may represent a novel therapeutic target for the clinical management of heart failure.
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PMID:Urotensin-II-mediated cardiomyocyte hypertrophy: effect of receptor antagonism and role of inflammatory mediators. 1554 73

Urotensin-II (U-II) is a vasoactive factor with pleiotropic effects. U-II exerts its activity by binding to a G-protein-coupled receptor termed UT. U-II and its receptor are highly expressed in the cardiovascular system. Increased U-II plasma levels have been reported in patients with cardiovascular disease of varying etiologies. We and others have shown that U-II and UT expression is elevated in both clinical and experimental heart failure and atherosclerosis. U-II induces cardiac fibrosis by increasing fibroblast collagen synthesis. In addition, U-II induces cardiomyocyte hypertrophy and increased vascular smooth muscle cell proliferation. We have shown that U-II antagonism using a selective U-II blocker, SB-611812 reduces neointimal thickening and increases lumen diameter in a rat restenosis model of carotid artery angioplasty. These findings suggest an important role for U-II in cardiovascular dysfunction and remodeling.
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PMID:Urotensin-II and cardiovascular diseases. 1713 7

Diastole plays a central role in cardiovascular homeostasis. Its two main determinants, myocardial relaxation and passive properties of the ventricular wall, are nowadays regarded as physiological mechanisms susceptible of active modulation. Furthermore, diastolic dysfunction and heart failure with normal ejection fraction (previously called diastolic heart failure) are two subjects of major clinical relevance and an intense area of research. The role of several neurohumoral mediators like angiotensin-II and endothelin-1 on the modulation of diastolic function was systematically described as having only chronic deleterious effects such as cardiac hypertrophy and fibrosis. However, over the last years a growing body of evidence described a new role for several peptides on the acute modulation of diastolic function. In the acute setting, some of these mediators may have the potential to induce an adaptive cardiac response. In this review, we describe the role of angiotensin-II, endothelin-1, nitric oxide, urotensin-II and ghrelin on the acute modulation of diastolic function, emphasizing its pathophysiological relevance. Only a thorough understanding of diastolic physiology as well as its active modulation, both in the acute and chronic settings, will improve our knowledge on diastolic dysfunction and allow us to solve the enigmas of heart failure with normal ejection fraction.
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PMID:Acute neurohumoral modulation of diastolic function. 1902 35

The vasoactive peptide urotensin-II (U-II) is likely to play a key causal role in cardiac remodeling that ultimately leads to heart failure. Its contribution, specifically to the development of diastolic dysfunction and the downstream intracellular signaling, however, remains unresolved. This study interrogates the effect of chronic U-II infusion in normal rats on cardiac structure and function. The contribution of Rho kinase (ROCK) signaling to these pathophysiological changes is evaluated in cell culture studies. Chronic high-dose U-II infusion over 4 wk significantly impaired diastolic function in rats on echocardiography-derived Doppler indexes, including E-wave deceleration time (vehicle 56.7 +/- 3.3 ms, U-II 118.0 +/- 21.5 ms; P < 0.01) and mitral valve annulus peak early/late diastolic tissue velocity (vehicle 2.01 +/- 0.19 ms, U-II 1.04 +/- 0.25 ms; P < 0.01). A lower dose of U-II infusion (1 nmol.kg(-1).h(-1)) yielded comparable changes. Diastolic dysfunction was accompanied by molecular [significant increases in procollagen-alpha(1)(I) gene expression on real-time PCR] and morphological (increases in total collagen, P < 0.05, and collagen type-I protein deposition, P < 0.001) evidence of left ventricular (LV) fibrosis following high-dose U-II infusion. The ROCK inhibitor GSK-576371 (10(-7) to 10(-5) M) elicited concentration-dependent inhibition of U-II (10(-7) M)-stimulated cardiac fibroblast collagen synthesis and cardiac myocyte protein synthesis. Chronic U-II infusion causes diastolic dysfunction, caused by fibrosis of the LV. The in vitro data suggest that this may be in part occurring via a ROCK-dependent pathway.
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PMID:Chronic urotensin-II infusion induces diastolic dysfunction and enhances collagen production in rats. 2000 68


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