Urocortin Neuropeptide Levels Are Impaired in the PBMCs of Overweight Children.

The corticotropin-releasing hormone (CRH) and urocortins (UCNs) have been implicated in energy homeostasis and the cellular stress response. However, the expression of these neuropeptides in children remains unclear. Therefore, we determined the impact of obesity on their expression in 40 children who were normal weight, overweight, and had obesity. Peripheral blood mononuclear cells (PBMCs) and plasma were used to assess the expression of neuropeptides. THP1 cells were treated with 25 mM glucose and 200 µM palmitate, and gene expression was measured by real-time polymerase chain reaction (RT-PCR). Transcript levels of neuropeptides were decreased in PBMCs from children with increased body mass index as indicated by a significant decrease in UCN1, UCN3, and CRH mRNA in overweight and obese children. UCN3 mRNA expression was strongly correlated with UCN1, UCN2, and CRH. Exposure of THP1 cells to palmitate or a combination of high glucose and palmitate for 24 h increased CRH, UCN2, and UCN3 mRNA expression with concomitant increased levels of inflammatory and endoplasmic reticulum stress markers, suggesting a crosstalk between these neuropeptides and the cellular stress response. The differential impairment of the transcript levels of CRH and UCNs in PBMCs from overweight and obese children highlights their involvement in obesity-related metabolic and cellular stress.

Urocortins as biomarkers in cardiovascular disease.

The urocortins (Ucns) belong to the corticotropin-releasing factor (CRF) family of peptides and have multiple effects within the central nervous and the cardiovascular systems. With growing evidence indicating significant cardioprotective properties and cardiovascular actions of these peptides, the question arises as to whether the plasma profiles of the Ucns are altered in pathologic settings. While reports have shown conflicting results and findings have not been corroborated in multiple independent cohorts, it seems likely that plasma Ucn concentrations are elevated in multiple cardiovascular conditions. The degree of increase and accurate determination of circulating values of the Ucns requires further validation.

Evaluation of Serum Urocortin 2 Levels in Patients with Hypertension.

INTRODUCTION: Urocortin 2 (UCN2), is an endogenous stress-related peptide belonging to the corticotropin-releasing factor (CRF) family, has a major role in the pathogenesis of congestive heart failure, ischemic heart disease, and hypertension. AIM: To investigate the role of UCN2 levels in patients with hypertension (HTN). METHODS: Serum UCN2 levels measured by ELISA were compared between patients with HTN (n = 86) and nonHTN (n = 53). RESULTS: Eighty-six patients with HTN [median age 66 (45-76); 38 men] and 53 patients with non-HTN [median age 62 (40-80); 39 men] were included into this study. Serum UCN2 (5.17 ng/ml; IQR, 1.26-11.68 ng/ml vs 0.79 ng/ml; IQR, 0.07-4.10 ng/ml, p < 0.0005) levels were found significantly elevated in patients with HTN compared to nonHTN control group. Concentrations of serum UCN2 were positively correlated with left ventricle mass index to body surface area (LV mass index to BSA, r = 0.20, p = 0.03), LV mass index to height2.7 (r = 0.28, p = 0.002) and body mass index (r = 0.24, p = 0.008). Additionally, logistic regression analysis was performed to UCN2, uric acid, creatinine, glomerular filtration rate, age, body mass index, coronary artery disease and diabetes mellitus which are the potential confounders of hypertension. According to logistic regression analysis serum UCN2 values were found out as an independent predictor of HTN. CONCLUSION: UCN2 levels, correlated with LV mass index were increased in HTN patients compared to nonHTN patients. These data provide evidence that there could be a relationship between high concentrations of UCN2 and HTN. UCN2 may appear as a promising choice of HTN treatment in the future.

Increased urocortin 3 levels are associated with the risk of having type 2 diabetes mellitus.

BACKGROUND: Urocortin 3 (UCN3) is a peptide hormone playing a pivotal role in glucose and lipid metabolisms. However, its clinical implications remain unclear. Our aims were to investigate the altered levels of UCN3 in newly diagnosed type 2 diabetes mellitus (nT2DM) patients in comparison to subjects with normal glucose tolerance (NGT) and to determine the presence of any possible link between UCN3 levels and metabolic parameters. METHODS: Eighty nT2DM and 80 age-, body mass index (BMI)-, and gender-matched NGT subjects were enrolled into this case-control study. The circulating UCN3 levels were measured using the enzyme-linked immunoabsorbent assay (ELISA). Metabolic parameters of enrolled subjects were also determined. A standard 75-g 2-hour oral glucose tolerance test was used for diagnosis of type 2 diabetes mellitus (T2DM). RESULTS: UCN3 levels were higher in subjects with nT2DM than in controls (115.64 ± 39.26 vs 86.16 ± 22.81 pg/mL, P < .001). UCN3 levels were increased in subjects with metabolic syndrome compared to subjects without metabolic syndrome in both nT2DM and NGT groups. UCN3 levels showed a positive correlation with BMI in both groups. Moreover, UCN3 levels were positively and independently associated with insulin, fasting blood glucose, insulin resistance, 2-hour plasma glucose, glycosylated hemoglobin, and triglycerides, whereas UCN3 levels were negatively and independently associated with high-density lipoprotein cholesterol. According to logistic regression analysis, increased risk of T2DM and metabolic syndrome were parallel with the highest elevated levels of UCN3. CONCLUSIONS: Increased levels of UCN3 are associated with unfavorable metabolic profiles in T2DM, indicating a potential role of UCN3 in glucose and lipid metabolisms in T2DM.

Urocortin 2 Gene Transfer Improves Heart Function in Aged Mice.

Prevalence of left ventricular (LV) systolic and diastolic dysfunction increases with aging. We previously reported that urocortin 2 (Ucn2) gene transfer increases heart function in mice with heart failure with reduced ejection fraction. Here, we test the hypotheses that (1) Ucn2 gene transfer will increase LV function in aged mice and that (2) Ucn2 gene transfer given in early life will prevent age-related LV dysfunction. Nineteen-month-old (treatment study) and 3-month-old (prevention study) mice received Ucn2 gene transfer or saline. LV function was examined 3-4 months (treatment study) or 20 months (prevention study) after Ucn2 gene transfer or saline injection. In both the treatment and prevention strategies, Ucn2 gene transfer increased ejection fraction, reduced LV volume, increased LV peak -dP/dt and peak +dP/dt, and reduced global longitudinal strain. Ucn2 gene transfer-in both treatment and prevention strategies-was associated with higher levels of LV SERCA2a protein, reduced phosphorylation of LV CaMKIIa, and reduced LV α-skeletal actin mRNA expression (reflecting reduced cardiac stress). In conclusion, Ucn2 gene transfer restores normal cardiac function in mice with age-related LV dysfunction and prevents development of LV dysfunction.

Disrupted compensatory response mediated by Wolfram syndrome 1 protein and corticotrophin-releasing hormone family peptides in early-onset intrahepatic cholestasis pregnancy.

INTRODUCTION: The most adverse perinatal outcome of intrahepatic cholestasis of pregnancy (ICP) is sudden fetal death related to acute fetoplacental hypoxia. Corticotrophin-releasing hormone (CRH), urocortin (UCN), and Wolfram syndrome 1 (WFS1) proteins may have a compensatory response to hypoxic stress. METHODS: A total of 108 singleton pregnant women were divided into three groups: control, late-onset ICP, and early-onset ICP. Enzyme-linked immunosorbent assays were used to detected maternal serum CRH, UCN, and WFS1 levels. Western blotting and real-time polymerase chain reaction were conducted to quantify placental protein and mRNA levels of CRH, UCN, and WFS1. Pearson correlation scatterplots and Pearson correlation matrix were employed to testify the correlation. RESULTS: Placental WFS1 had a positive relation with placental UCN (r = 0.69, P < 0.05) and serum UCN (r = 0.36, P < 0.05). Placental CRH was positively correlated with maternal serum CRH (r = 0.53, P < 0.05). Maternal serum and placental levels of CRH, UCN, and WFS1 significantly increased in the early-onset ICP group compared with the control group (P < 0.05). Placental levels of UCN and WFS1 in the early-onset ICP group were significantly elevated and higher in comparison with the late-onset ICP group (P < 0.05). However, the transcriptional levels of CRH, UCN, and WFS1 were impaired in the early-onset ICP group. DISCUSSION: Our study revealed that transcription and translation of WFS1, CRH, and UCN were altered during pregnancies complicated by early-onset ICP. This disrupted compensatory response mediated by WFS1 and CRH family peptides in early-onset ICP may play a significant role in the pathogenesis of sudden fetal death in acute fetal hypoxia.

Plasma urocortin-1 as a preoperative marker of endometriosis in symptomatic women.

Accurate noninvasive diagnostic tests for endometriosis are still missing. This study evaluated the predictive value of the neuropeptide urocortin 1 (Ucn1) to detect pelvic endometriosis in symptomatic women. We enrolled prospectively 97 consecutive women submitted to gynecologic laparoscopy for chronic or acute pelvic pain, infertility or adnexal mass. Preoperative blood samples were assayed for Ucn1 using enzyme immunoassay. Patients with endometriosis had higher plasma Ucn1 levels compared to patients with no lesions (median 59 vs. 34 pg/ml, p < .01, Dunn's test). Elevated plasma Ucn1 levels were found among all endometriosis phenotypes (superficial peritoneal lesions, ovarian endometrioma, and deep infiltrating endometriosis, p < .05 vs. no lesions). Receiver operating characteristics curve analysis identified plasma Ucn1 > 46 pg/mL as the best cutoff point to detect endometriosis vs. no lesions, with 76% sensitivity and 88% specificity (area under the curve [AUC] 0.827, 95% confidence interval [CI] 0.695 - 0.959), but no cutoff could accurately distinguish endometriosis from other pathological conditions (AUC 0.593 [95% CI 0.474 - 0.711]). In women with chronic pelvic pain, infertility, or both symptoms, the probability of endometriosis (positive predictive value) increased consistently with the increase of plasma Ucn1 levels. The present findings suggest that high plasma Ucn1 levels increase the likelihood of endometriosis in symptomatic women.

Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction.

Heart failure occurs when the heart is unable to effectively pump blood and maintain tissue perfusion. Despite numerous therapeutic advancements over previous decades, the prognosis of patients with chronic heart failure remains poor, emphasizing the need to identify additional pathophysiological factors. Here, we show that corticotropin releasing hormone receptor 2 (Crhr2) is a G protein-coupled receptor highly expressed in cardiomyocytes and continuous infusion of the Crhr2 agonist, urocortin 2 (Ucn2), reduced left ventricular ejection fraction in mice. Moreover, plasma Ucn2 levels were 7.5-fold higher in patients with heart failure compared to those in healthy controls. Additionally, cardiomyocyte-specific deletion of Crhr2 protected mice from pressure overload-induced cardiac dysfunction. Mice treated with a Crhr2 antagonist lost maladaptive 3'-5'-cyclic adenosine monophosphate (cAMP)-dependent signaling and did not develop heart failure in response to overload. Collectively, our results indicate that constitutive Crhr2 activation causes cardiac dysfunction and suggests that Crhr2 blockade is a promising therapeutic strategy for patients with chronic heart failure.

The evaluation of the clinical utility of urocortin 1 and adrenomedullin versus proBNP in systolic heart failure.

OBJECTIVE: Urocortin 1 (UCN1) has vasodilator, diuretic, and natriuretic effects, and its expression increases in heart failure (HF). Adrenomedullin (ADM) increases cardiac output and lowers blood pressure in healthy men and in patients with heart failure. The aim of the study was to determine UCN1 and ADM levels in patients with HF, to evaluate the relationship of UCN1 and ADM with various clinical parameters, and to assess UCN1 and ADM as diagnostic markers in HF, in comparison with pro-brain natriuretic peptide (pro-BNP). METHODS: We investigated serum levels of UCN1, ADM, and pro BNP in 86 consecutive patients with systolic HF [ejection fraction (EF) ≤45%] and 85 healthy controls. Serum UCN1, ADM, and pro-BNP levels were measured with the ELISA method. Transthoracic echocardiography was performed to determine left ventricular EF and pulmonary artery systolic pressure. RESULTS: UCN1 and ADM levels were higher in HF patients (446.2±145.7 pg/mL, p<0.001; 87.9±4.2 pg/mL, p<0.001 respectively). UCN1 was positively correlated with pro-BNP (r=0.963, p<0.001), ADM (r=0.915, p<0.001), and NYHA (r=0.879, p<0.001); ADM was positively correlated with pro-BNP (r=0.956, p<0.001) and NYHA (r=0.944, p<0.001). Receiver operating characteristic curves yielded an area under the curve of 1.00 (p<0.001) for UCN1, 1.00 (p<0.001) for ADM, and 0.99 (p<0.001) for pro-BNP in the diagnosis of HF. CONCLUSION: UCN1 and ADM increase with worsening HF and left ventricular dysfunction. They may be used as diagnostic biomarkers in systolic HF, but the incremental value of measuring UCN1 and ADM in patients tested for pro-BNP is questionable.

The relationship of urocortin-2 with insulin resistance patients having PCOS.

In this study, we aimed to compare the serum urocortin-2 (UCN2) levels in women with polycystic ovary syndrome (PCOS) and healthy women. Thirty-eight patients with PCOS and 41 healthy women were included in the study whose age and BMI matched. The fasting serum glucose, insulin, free testosterone, hs-CRP and UCN2 levels of the all participants were examined. HOMA-IR formula was used in order to calculate the insulin resistance. Circulating UCN2 levels were significantly elevated in women with PCOS compared with controls (142.93 ± 59.48 versus 98.56 ± 65.01 pg/ml, p = 0.002). FBG, serum insulin, hs-CRP and HOMA-IR levels were found to be increased in women with PCOS. There was a positive correlation between UCN2 and free-testosterone in only PCOS group (r = 0.235, p = 0.027). Multivariate logistic regression analyses revealed that the odds ratio for PCOS was 2.31 for patients in the highest quartile of UCN2 compared with those in the lowest quartile (OR = 2.31, 95% CI = 1.88-2.83, p=0.021). Multiple linear regression analysis revealed that HOMA-IR, hs-CRP and free-testosterone independently predicted UCN2 levels (p < 0.05). UCN2 levels were significantly higher in PCOS cases when compared to control group. UCN2 is thought to be effective on pathophysiology of PCOS by paracrine and autocrine pathways.

Dynamic expression of corticotropin-releasing hormone and urocortin in estrogen induced-cholestasis pregnant rat.

Intrahepatic cholestasis of pregnancy(ICP) is complicated by acute placental-fetal hypoxia. Corticotropin-releasing hormone(CRH) and urocortin(UCN) are vasodilatory regulators of blood flow in the placenta. An ethinylestradiol(EE)-induced cholestasis rat model was reproduced and serum/placental CRH/UCN were detected during 14-21days of gestation(DG). Maternal serum or placental CRH/UCN levels in the control rats were relatively consistent during 14-21DG. Serum CRH was reduced in the EE-treated rats compared with the control rats at 21DG. Regarding serum UCN, we observed a decrease at 17DG as well as an increase at 21DG in the EE-treated rats compared with the controls. Moreover, we observed a noticeable reduction of placental CRH/UCN expression at 17 or 19DG in the EE-treated rats compared with the control rats. The serum bile acids levels exhibited an inverse correlation with placental CRH/UCN expression. EE-induced cholestasis rats might serve as a good model to further investigate the pathological mechanism underlying CRH/UCN dysregulation in ICP.

High-Sensitivity Sandwich ELISA for Plasma NT-proUcn2: Plasma Concentrations and Relationship to Mortality in Heart Failure.

BACKGROUND: Urocortin 2 (Ucn2) has powerful hemodynamic, renal, and neurohormonal actions and likely participates in normal circulatory homeostasis and the compensatory response to heart failure (HF). A validated assay for endogenous circulating Ucn2 would facilitate investigations into Ucn2 physiology and elucidate its derangement and potential as a biomarker in heart disease. METHOD: We developed a chemiluminescence-based sandwich ELISA to measure plasma N-terminal (NT)-proUcn2 in non-HF patients (control; n = 160) and HF patients with reduced (HFREF; n = 134) and preserved (HFPEF; n = 121) left ventricular ejection fraction (LVEF). RESULTS: The ELISA had a limit of detection of 8.47 ng/L (1.52 pmol/L) and working range of 23.8-572 ng/L. Intra- and interassay CV and total error were 4.8, 16.2, and 17.7%, respectively. The median (interquartile range) plasma NT-proUcn2 concentration in controls was 112 (86-132) ng/L. HFREF, HFPEF, and all HF plasma concentrations were significantly increased [117 (98-141) ng/L, P = 0.0007; 119 (93-136) ng/L, P = 0.0376, and 119 (97-140) ng/L, P = 0.001] compared with controls but did not differ significantly between HFREF and HFPEF. NT-proUcn2 was modestly related to age (r = 0.264, P = 0.001) and cardiac troponin T (r = 0.258, P = 0.001) but not N-terminal pro-B-type natriuretic peptide, body mass index, LVEF, or estimated glomerular filtration rate. On multivariate analysis, plasma NT-proUcn2 was independently and inversely related to 2-year mortality in HF. CONCLUSIONS: The validated ELISA measured human NT-proUcn2 in plasma and showed modest but significant increases in HF patients compared with controls. In HF, the unusual inverse relationship between plasma NT-proUcn2 and 2-year mortality portends potential prognostic value but requires further corroboration.

Increased circulating urocortin-3 levels is associated with polycystic ovary syndrome.

This study was aimed to compare serum urocortin-3 (UCN3) levels in women with polycystic ovary syndrome (PCOS) and healthy women, and establish what role UCN3 levels play in PCOS. Fifty-two patients with PCOS and 55 healthy women were included in the study, matched for age and body mass index. Fasting blood glucose (FBG), insulin, hs-CRP, UCN3 and free-testosterone levels of the all participants were measured. HOMA-IR was used to calculate the insulin resistance. Circulating UCN3 levels were significantly increased in women with PCOS than in control subjects (54.49 ± 5.77 versus 51.28 ± 5.86 pmol/l, p = 0.005). Serum insulin, hs-CRP and HOMA-IR levels were higher in women with PCOS than in control group. UCN3 levels positively correlated with hs-CRP in PCOS group (r = 0.391, p = 0.004). Receiver operating characteristic (ROC) curve analysis showed that the area under the ROC curves were 0.732 (95% CI 0.634-0.830, p < 0.001) for UCN3 levels. The optimal cut-off value of UCN3 for detecting PCOS was ≥51.46 pmol/l, at which the sensitivity was 75% and specificity was 68%. Our results suggest that there is a potential link between PCOS and UCN3 levels. The results of this study support the presence of increased UCN3 levels for the association of inflammation with PCOS.

Novel markers in the diagnostics of endometriomas: Urocortin, ghrelin, and leptin or leukocytes, fibrinogen, and CA-125?

OBJECTIVE: CA-125 protein is used as a marker in clinical practice for the diagnosis of endometriomas. The aim of this study was to determine whether endometriomas are accompanied by an increased level of urocortin, ghrelin, and leptin, as well as the increased parameters of blood cell count, fibrinogen, and CA-125. MATERIALS AND METHODS: The study included 86 women aged 18-38 years who had been treated laparoscopically for lesions in the adnexa with the characteristics of endometriomas and mature teratoma, during the period September 2009 to November 2012. The statistical analysis was performed using the nonparametric Mann-Whitney U test and the Spearman rank correlation coefficients (p ≤ 0.05). RESULTS: The medians were 105.31 pg/mL versus 120.84 pg/mL for urocortin, 7.16 pg/mL versus 9.13 pg/mL for leptin and 584.33 pg/mL versus 657.82 pg/mL for ghrelin (p > 0.05), respectively. Analyzing the parameters of blood cell count, statistically significant differences were shown in the respective groups for leucocyte level (5.35 × 10(9)/L vs. 6.7 × 10(9)/L; p = 0.029), fibrinogen level (3.12 mg% vs. 2.57 mg%; p = 0.001), and CA-125 (36.50 U/mL vs. 15.08 U/mL; p = 0.001). CONCLUSION: In conclusion, the prognostic values for CA-125, leukocytes, and fibrinogen may prove a very useful tool for the diagnosis of lesions in the adnexa of the type endometriomas.

[Decreased maternal plasma urocortin level in intrahepatic cholestasis of pregnancy].

OBJECTIVE: To measure the plasma level of urocortin and the placenta expression of its receptor corticotropin-releasing hormone receptor (CRHR)-2 in the patients with intrahepatic cholestasis of pregnancy (ICP). METHODS: This study enrolled 20 patients with ICP and 20 normal pregnant women (control group). The plasma level of urocortin at different gestational age (34-37 weeks) was measured by enzyme-linked immunosorbent assay (ELISA), and the placenta expression of CRHR-2 was investigated by immunohistochemical technique. RESULTS: The plasma urocortin levels at different gestational age in normal pregnany were (79.47 +/- 11.35) pg/mL at 34 weeks, (83.00 +/- 12.67) pg/mL at 35 weeks, (80.28 +/- 11.48) pg/mL at 36 weeks, and (84.24 +/- 13.62) pg/mL at 37 weeks, respectively. No upward tendency was observed along with the increase of gestational age (F= 0.67, P>0.05). Compared with normal pregnany, ICP patients had novel down trend of the plasma urocortin levels (F = 6.78, P<0.05), which were (68.53 +/- 16.95) pg/mL at 34 weeks, (64. 19+22. 50) pg/mL at 35 weeks, (50.06 +/- 13.98) pg/mL at 36 weeks, (47.91 +/- 15.65) pg/mL at 37 weeks, CRHR-2 staining was found in syncytiotrophoblast and feto-placental vascular endothelium cells of placenta, and there was no statistical differences found for integral optical density value of CRHR-2 staining between control (101.09 +/- 27.21) and ICP (111.83 +/- 35.02) groups (P>0.05). CONCLUSION: The urocortin-mediated stress compensation insufficiency may be involved in the fetal outcomes in ICP.

Diagnostic capability of biological markers in assessment of obstructive sleep apnea: a systematic review and meta-analysis.

OBJECTIVE: The purpose of this systematic review is to evaluate the diagnostic value of biological markers (exhaled breath condensate, blood, salivary and urinary) in the diagnosis of OSA in comparison to the gold standard of nocturnal PSG. METHODS: Studies that differentiated OSA from controls based on PSG results, without age restriction, were eligible for inclusion. The sample of selected studies could include studies in obese patients and with known cardiac disease. A detailed individual search strategy for each of the following bibliographic databases was developed: Cochrane, EMBASE, MEDLINE, PubMed, and LILACS. The references cited in these articles were also crosschecked and a partial grey literature search was undertaken using Google Scholar. The methodology of selected studies was evaluated using the 14-item Quality Assessment Tool for Diagnostic Accuracy Studies. RESULTS: After a two-step selection process, nine articles were identified and subjected to qualitative and quantitative analyses. Among them, only one study conducted in children and one in adults found biomarkers that exhibit sufficiently satisfactory diagnostic accuracy that enables application as a diagnostic method for OSA. CONCLUSION: Kallikrein-1, uromodulin, urocotin-3, and orosomucoid-1 when combined have enough accuracy to be an OSA diagnostic test in children. IL-6 and IL-10 plasma levels have potential to be good biomarkers in identifying or excluding the presence of OSA in adults.

Expression of urocortin and corticotrophin-releasing hormone receptor-2 in patients with intrahepatic cholestasis of pregnancy.

INTRODUCTION: Intrahepatic cholestasis of pregnancy (ICP) is associated with an increased risk of adverse pregnancy outcomes. Fetal distress in ICP is an acute process, and the abnormal expression of placental local vasodilatory factors play an essential role. Urocortin (UCN) exhibits a powerful concentration-dependent vasodilatation effect in the utero-placental-fetal unit. Our study aimed to investigate placental and serum UCN expression in ICP patients. METHODS: Blood and placenta samples were obtained from the ICP patients and controls. UCN and corticotrophin-releasing hormone receptor-2 (CRH-R2) expression were detected by ELISA, immunohistochemistry, Western Blotting and real-time PCR. RESULTS: Placental UCN expression of ICP was lower compare to the controls (0.27 ± 0.11 vs. 0.85 ± 0.21) (P < 0.05). Placental CRH-R2 (0.97 ± 0.09 vs. 0.86 ± 0.09) showed no difference between the ICP and controls (P > 0.05). Placental UCN mRNA (1.45 ± 0.31 vs. 0.72 ± 0.29) and CRH-R2 mRNA expression (1.11 ± 0.10 vs. 0.84 ± 0.24) were higher compared to the controls (all P < 0.05). Maternal serum UCN levels demonstrated no difference from 34 (79.47 ± 11.35 pg/ml) to 37 (84.24 ± 13.62 pg/ml) weeks of gestation in controls (P > 0.05). Maternal serum UCN levels of ICP were decreased from 34 (68.53 ± 16.95 pg/ml) to 37 (47.91 ± 15.65 pg/ml) weeks of gestation (P < 0.05) and were lower than controls at 35 (64.19 ± 22.50 pg/ml), 36 (50.06 ± 13.98 pg/ml) and 37 weeks of gestation (all P < 0.05). DISCUSSION: The down-regulated UCN expression in the placenta and maternal serum during ICP may impair the blood flow regulation of the utero-placental-fetal unit and contribute to fetal distress. Maternal serum UCN levels might represent a potential clinical predictor of adverse fetal outcomes and optimize the clinical management.

Evaluation of the clinical utility of urocortin 1 in systolic heart failure.

BACKGROUND: Urocortin 1 (UCN1) has cardiostimulatory, vasodilatory, diuretic and natriuretic effects, and its expression increases in heart failure (HF). AIM: To determine UCN1 levels in patients with HF, to evaluate UCN1's relationship with various clinical parameters, and to assess UCN1 as a diagnostic marker in HF, compared to pro-B-type natriuretic peptide (pro-BNP). METHODS: We investigated serum levels of UCN1 and pro-BNP in 90 consecutive patients with systolic HF (left ventricular ejection fraction [LVEF] ≤ 45%) and 90 healthy controls. Serum UCN1 and pro-BNP levels were measured using the ELISA method. Transthoracic echocardiography was performed to determine LVEF and pulmonary artery systolic pressure (PASP). Glomerular filtration rate (GFR) was estimated using the Cockcroft-Gault formula. RESULTS: UCN1 level was higher in HF patients (391.5 [357.0-482.0] pg/mL, p < 0.001). UCN1 was positively related with NYHA class (r = 0.89, p < 0.001), and PASP (r = 0.39, p < 0.001); and negatively related with LVEF (r = -0.46, p < 0.001), and GFR (r = -0.21, p = 0.046). A significant positive correlation was found between pro-BNP and UCN1 levels (p < 0.001, r = 0.96). Receiver operating characteristic (ROC) curves yielded an area under the curve (AUC) of 0.99 (95% CI 0.98-1.00,p < 0.001) for UCN1 and 1.00 (p < 0.001) for pro-BNP in the diagnosis of HF. CONCLUSIONS: UCN1 increases with worsening HF and left ventricular dysfunction. It may be used as a diagnostic biomarker in systolic HF, but the incremental value of measuring UCN1 in patients tested for pro-BNP is questionable.

Urocortin 2 is associated with abdominal aortic aneurysm and mediates anti-proliferative effects on vascular smooth muscle cells via corticotrophin releasing factor receptor 2.

AAA (abdominal aortic aneurysm) is an important cause of sudden death in older adults, but there is no current effective drug therapy for this disease. The UCNs (urocortins1-3) and their receptors: CRFR (corticotrophin-releasing factor receptor)-1 and -2 have been implicated in various CVDs (cardiovascular diseases). We assessed the relative expression of UCN1-3 in AAA by qRT-PCR (quantitative reverse transcription-PCR) and ELISA, and examined in vitro how UCN2 affects human aortic VSMC (vascular smooth muscle cell) Akt phosphorylation, pro-inflammatory cytokine IL (interleukin)-6 secretion, proliferation, cell cycle and apoptosis. UCN2 and CRFR2 expression were significantly up-regulated in biopsies from the AAA body. AAA body biopsies released high amounts of UCN2 in vitro. Median plasma UCN2 concentrations were 2.20 ng/ml (interquartile range 1.14-4.55 ng/ml, n=67) in AAA patients and 1.11 ng/ml (interquartile range 0.76-2.55 ng/ml, n=67) in patients with non-aneurysmal PAD (peripheral artery disease) (P=0.001). Patients with UCN2 in the highest quartile had a 4.12-fold (95% confidence interval, 1.37-12.40) greater prevalence of AAA independent of other risk factors, P=0.012. In vitro, UCN2 significantly inhibited VSMC Akt phosphorylation and proliferation in a dose-dependent manner. UCN2 induced VSMC G1 cell-cycle arrest and increased IL-6 secretion over 24 h. The CRFR2 antagonist astressin-2B significantly abrogated the effects of UCN2 on VSMCs. In conclusion, UCN2 is significantly associated with AAA and inhibits VSMC proliferation by inducing a G1 cell cycle arrest suggesting a plausible regulatory role in AAA pathogenesis.

Estrogens downregulate urocortin 2 expression in rat uterus.

Urocortin 2 (Ucn2) is a member of the corticotropin-releasing factor peptide family and is expressed by various tissues, including reproductive tissues such as the uterus, ovary, and placenta. However, the regulatory mechanisms of Ucn2 expression and the physiological significance of Ucn2 in these tissues remain unclear. We previously showed that passive immunization of immature female rats by i.p. injection of anti-Ucn2 IgG induces earlier onset of puberty. Therefore, this study was designed to clarify the site and regulatory mechanisms of Ucn2 expression in the uterus. Expression levels of Ucn2 mRNA in the uterus were higher in immature (2- and 4-week-old) and aged (17-month-old) rats than in mature (9-week-old) rats in the proestrus phase. In 9-week-old rats, mRNA expression levels and contents in the uterus were lower in the proestrus phase than in the diestrus phase, while plasma Ucn2 concentrations did not differ between the two phases. Ucn2-like immunoreactivitiy was detected in the endometrial gland epithelial cells of the uterus. S.c. injection of estradiol benzoate or an estrogen receptor α (ERα) agonist significantly reduced mRNA expression levels and contents of Ucn2 in the uterus when compared with vehicle-injected ovariectomized rats. By contrast, estradiol benzoate increased Ucn2 mRNA expression levels in the lung. Thus, estrogens downregulate Ucn2 expression in the uterus in a tissue-specific manner, and Ucn2 may play a role in the regulatory mechanisms of maturation of the uterus through ERα and estrous cycle.