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Background and aims: The aims of the present study were to determine the expression of urotensin II (UII), urotensin-II related peptide (URP) and their receptor (UT) in stable and unstable carotid atherosclerosis, and determine the effects of UII on human aortic smooth muscle cell (SMCs) calcification.Methods and Results: We examined UII, URP and UT protein expression in 88 carotid endarterectomy specimens using immunohistochemistry. Expression of UII, URP and UT was more evident in unstable compared to stable plaques (P

Exercise is beneficial for a variety of age-related disorders. However, the molecular mechanisms mediating the beneficial adaptations to exercise in older adults are not well understood. The aim of the current study was to utilize a dual approach to characterize the genetic and metabolic adaptive pathways altered by exercise in veteran athletes and age-matched untrained individuals. Two groups of 50-60 year old males: competitive cyclists (athletes, n = 9; VO2peak 59.1±5.2 ml·kg(-1)·min(-1); peak aerobic power 383±39 W) and untrained, minimally active individuals (controls, n = 8; VO2peak 35.9±9.7 ml·kg(-1)·min(-1); peak aerobic power 230±57 W) were examined. All participants completed an acute bout of submaximal endurance exercise, and blood and urine samples pre- and post-exercise were analyzed for gene expression and metabolic changes utilizing genome-wide DNA microarray analysis and NMR spectroscopy-based metabolomics, respectively. Our results indicate distinct differences in gene and metabolite expression involving energy metabolism, lipids, insulin signaling and cardiovascular function between the two groups. These findings may lead to new insights into beneficial signaling pathways of healthy aging and help identify surrogate markers for monitoring exercise and training load.

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-l. For example, both compounds elicit a strong vascular smooth muscle-dependent vasoconstriction via [Ca.sup.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. UT receptor; somatostatin; human; experimental animals; autocrine/paracrine doi: 10.1152/ajpregu.00706.2009.

Urotensin-II (UII), which binds to its receptor UT, plays an important role in the heart, kidneys, pancreas, adrenal gland and CNS. In the vasculature, it acts as a potent endothelium-independent vasoconstrictor and endothelium-dependent vasodilator. In disease states, 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 ACAT-1 activity leading to SMC 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.

Inhibition of NOS II prevents cardiac dysfunction in myocardial infarction and congestive heart failure. Am J Physiol Heart Circ Physiol 283: H339-H345, 2002. First published February 14, 2002; 10.1152/ajpheart.00596.2001.---Strong expression of the inducible form of nitric oxide synthase (NOS II) has been shown in the myocardium of patients with myocardial infarction (MI). We hypothesized that NOS II plays an important role in the development of MI and subsequent heart failure and that inhibition of NOS II may beneficially alter the course of the disease. Long-term administration (2 mo) of the selective NOS II inhibitor S-methylisothiourea (SMT) to rats with MI significantly improved cardiac function. A significant drop in mortality, lung water content, infarct size, and cardiomyocyte hypertrophy was also associated with the use of SMT. Plasma concentration of nitrite and nitrate was also reduced by SMT. Short-term administration of SMT (first 2 wk only) significantly reduced infarct size; however, it did not improve cardiac dysfunction measured 2 mo after MI. These findings demonstrate that induction of NOS II during MI exerts negative effects on cardiac function and structure. Long-term administration of a selective NOS II inhibitor may prove to be beneficial in the treatment of MI and congestive heart failure. S-methylisothiourea

Patients with pulmonary hypertension may have decreased production of nitric oxide synthase in the cells lining their blood vessels. Nitric oxide synthase is an enzyme that produces nitric oxide, which relaxes blood vessels and prevents the growth of the muscles lining blood vessels. Researchers analyzed the production of nitric oxide synthase in lung tissue of 22 patients with plexogenic pulmonary arteriopathy, 24 patients with pulmonary hypertension, and 23 patients with inflamed or normal lungs. The production of nitric oxide synthase was high in cells lining the normal lungs and their blood vessels. The production of the enzyme was low in lung blood vessels of patients with plexogenic pulmonary arteriopathy or pulmonary hypertension. Lower production of the enzyme was associated with blood vessels with high vascular resistance.

Natural and targeted piebald-lethal mutations in the endothelin-B receptor (EDNRB) gene in mouse cause aganglionic megacolon with coat color spotting in the mice. The recessive phenotype of the natural piebald-lethal (s') mutations is similar to that of targeted mutations, indicating that the EDNRB gene deletion localizes to the s' chromosome. The effects of the s' mutations indicate their involvement in the growth of two neural-crest-derived cell lineages, the epidermal melanocytes and the myenteric ganglion. Abnormalities in the human EDNRB gene initiate Hirschsprung's disease that is genetically mapped to chromosome 13 that consists of the EDNRB.

Targeted endothelin-3 ligand (EDN3) gene disruption in mice produces the same recessive phenotype of coat color spotting and megacolon as does the disruption of endothelin-B receptor gene. A natural recessive EDN3 gene mutation in lethal spotting (ls) mice does not complement the targeted EDN3 allele, indicating that ls is allelic to the EDN3 gene in the mice. A point gene mutation in the ls mice blocks the endothelin-converting enzyme induced proteolytic stimulations between endothelin-B receptor. Thus, interactions between endothelin-B and EDN3 are necessary for growth of neural crest-derived lineages.

Vascular endothelium is the expression site of endothelium-converting enzyme (ECE)-1 RNAs, which are required for the conversion of big ET-1 and the secretion of mature ET-1 from cells transfected with prepro-ET-1. High concentrations of phosphoramidon inhibit the activity of ECE, resulting in the accumulation of big ET-1 in the cells and suppression of mature ET-1 production. Therapeutic intervention of ECE-1 can aid the systemic alteration of ET-1 production.

Endothelin-1 may contribute to the development of several lung diseases, including pulmonary hypertension. Pulmonary hypertension is characterized by increasing resistance to blood flow in the pulmonary arteries and veins. Endothelin-1 is a substance produced by the lining of the blood vessels (the endothelium) that causes blood vessels to constrict. Samples of lung tissue were taken from 28 patients with pulmonary hypertension and 15 healthy people (the controls). Various tests were performed on the samples to detect endothelin-1 and its messenger RNA (mRNA). Microscopic examination of samples from the patients with pulmonary hypertension revealed that their arteries were thickened. Substantial amounts of endothelin-1 were found in these thickened arteries, while the control samples lacked endothelin-1. Endothelin-1 mRNA was also found in the patients' samples, but not in the control samples.