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Urotensin II (UTN), a cyclic undecapeptide widely distributed in various organs and tissues, is found in high concentration in atheromatous lesions. Because UTN accumulates in patients with chronic renal failure, the association between plasma UTN and biomarkers of atherosclerosis and endothelial activation needs to be better understood.We tested by a robust statistical approach (Holm method) the association between plasma UTN and biomarkers of atherosclerosis and endothelial activation in a population of 191 patients undergoing chronic hemodialysis.Plasma UTN was significantly higher in patients with end-stage renal disease (median: 6.5 ng/mL) than in healthy subjects (median: 3.1 ng/mL) (P < .001), and in both patients and control subjects it was independent of age and sex. Interestingly, UTN was inversely related to fibrinogen (r = −0.50, P < .004), intracellular adhesion molecule-1 (r = −0.24, P < .004) and with NO synthesis inhibitor asymmetric dimethyl-arginine (r = −0.40, P < .004). These links were paralleled by direct correlations with albumin (r = 0.21, P < .006) and with transforming growth factor-β1 (TGFβ1) (r = 0.36, P < .004). Of note, on multiple regression analysis, these associations remained highly significant also after data adjustment for potential confounders.The inverse links between UTN with biomarkers of atherosclerosis and endothelial activation suggest that downregulation of UTN may be a counter-regulatory response aimed at mitigating cardiovascular damage or that UTN itself is a protective factor.