Hormone treatments in congestive heart failure.

The common ultimate pathological feature for all cardiovascular diseases, congestive heart failure (CHF), is now considered as one of the main public health burdens that is associated with grave implications. Neurohormonal systems play a critical role in cardiovascular homeostasis, pathophysiology, and cardiovascular diseases. Hormone treatments such as the newly invented dual-acting drug valsartan/sacubitril are promising candidates for CHF, in addition to the conventional medications encompassing beta receptor blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists. Clinical trials also indicate that in CHF patients with low insulin-like growth factor-1 or low thyroid hormone levels, supplemental treatment with growth hormone or thyroid hormone seems to be cardioprotective; and in CHF patients with volume overload the vasopressin antagonists can relieve the symptoms superior to loop diuretics. Furthermore, a combination of selective glucocorticoid receptor agonist and mineralocorticoid receptor antagonist may be used in patients with diuretic resistance. Finally, the potential cardiovascular efficacy and safety of incretin-based therapies, testosterone or estrogen supplementation needs to be prudently evaluated in large-scale clinical studies. In this review, we briefly discuss the therapeutic effects of several key hormones in CHF.

Anxiolytic- and antidepressant-like actions of Urocortin 2 and its fragments in mice.

The aim of the present study was to investigate the potential anxiolytic- and antidepressant-like actions of Urocortin 2 (Ucn2) and its two fragments, Ucn2 (1-21) and Ucn2 (22-38), in mice, in an attempt to identify the biologically active sequence of this 38 amino acid neuropeptide. In this purpose, male C57BL/6 mice were treated intracerebroventricularly (icv) with 0.125, 0.25, 0.5 and 1 µg/2 µl of Ucn2, Ucn2 (1-21) or Ucn2 (22-38). After 30 min, the mice were evaluated in an elevated plus-maze test and a forced swim test for anxiety- and depression-like behavior, respectively. Each test lasted 5 min. Ucn2 at dose of 0.25 µg/2 µl and Ucn2 (1-21) at dose of 0.125 µg/2 µl, but not Ucn2 (22-38), increased significantly the number of entries into and the time spent in the open-arms, without influencing the total number of entries. In parallel, the same doses of Ucn2 and Ucn2 (1-21), but not Ucn2 (22-38), increased significantly the climbing and the swimming activity, while decreasing significantly the time of immobility. In addition, Ucn2 at doses of 0.125 µg/2 µl and 0.5 µg/2 µl decreased significantly the time of immobility, but they did not change the other parameters. The present study demonstrates that Ucn2 exerts anxiolytic- and antidepressant-like effects in C57BL/6 mice, which are mediated by the N-terminal, but not the C-terminal fragment of the peptide. The establishment of the smallest active sequence by further fragmentation of Ucn2 (1-21) may allow the synthesis of new anxiolytic and antidepressant drugs.

Urocortin 2 protects heart and kidney structure and function in an ovine model of acute decompensated heart failure: Comparison with dobutamine.

BACKGROUND: Renal dysfunction is a frequent complication and crucial determinant of outcome in acute decompensated heart failure (ADHF). The aim of the study was to assess urocortin 2 (Ucn2) as a short-term therapy in ADHF with a focus on its renal effects. Comparison was made with dobutamine to distinguish effects beyond pure inotropism. METHODS: Sheep with ADHF received a 2-day infusion of a vehicle-control, Ucn2 or dobutamine (n=6/grp). RESULTS: Compared to controls, Ucn2 and dobutamine produced matched improvements in cardiac contractility and output and arterial pressure, whereas reductions in central venous and left atrial pressures were greater with Ucn2. Both agents comparably repressed ADHF-activated hormone systems with the exception of the natriuretic peptides, which fell significantly during dobutamine but not Ucn2. While Ucn2 and dobutamine increased creatinine clearance and urine volume similarly, only Ucn2 induced a significant natriuresis. Ucn2 also decreased collagen deposition in the heart and kidney and suppressed gene expression of collagen-1, transforming growth factor-ß1, components of the angiotensin system (angiotensinogen, angiotensin-converting enzyme, type-1 receptor) and markers of hypertrophy (GATA binding protein-4, ß-myosin heavy chain), apoptosis (caspase3) and inflammation/injury (interleukin-18, cystatin C, neutrophil gelatinase-associated lipocalin, kidney injury molecule-1) in these tissues, while increasing cardiac natriuretic peptide mRNA. In contrast, dobutamine produced reduced or opposite effects on expression of these factors. CONCLUSIONS: Ucn2 administration in ADHF has favorable effects on hemodynamics, the natriuretic peptides and tissue mediators of inflammation, fibrosis, apoptosis and hypertrophy that stand in contrast to dobutamine. These data support Ucn2's potential as a renoprotective therapeutic in this setting.

The protective effects of urocortin1 against intracerebral hemorrhage by activating JNK1/2 and p38 phosphorylation and further increasing VEGF via corticotropin-releasing factor receptor 2.

Urocortin (UCN) has exhibited antiinflammatory and neuroprotective effects on intracerebral hemorrhage (ICH). However, the underlying mechanisms are still not clear. Therefore, this study was aimed to investigate effects of UCN1 on ICH in vitro and in vivo and further explore the possible mechanism. ICH was induced by an infusion of autologous blood into the unilateral striatum of anesthetized male Sprague-Dawley rats. The rats were randomly divided into three groups (8 rats per group): sham ICH control group, ICH saline group and ICH UCN1 group. UCN1 was infused into the lateral ventricle after 1h post-ICH. Neurological deficits were evaluated by modified neurological severity score (mNSS). Brain edema was assessed using the dry/wet method. The neurological cell metabolic activity of N2a and SH-SY5Y was detected by CCK-8. The level of VEGF, JNK and p38 were determined by enzyme-linked immunosorbent assay and western blot. Post-treatment with UCN1 could improve neurological deficits and reduce brain edema. Moreover, UCN1 could increase the metabolic activity of neuron cells dose-dependently and these effects could be abolished by corticotropin-releasing factor receptor 2 (CRFR2) antagonist anti-Svg-30. Furthermore, the level of VEGF, JNK and p38 were up-regulated by post-treatment with UCN1 via CRFR2. The protective effects of UCN1 against ICH are possibly mediated by activating the phosphorylation of JNK and p38 and further increasing the level of VEGF via CRFR2.

The localization of brain sites of anxiogenic-like effects of urocortin-2.

The influence of intracerebroventricullary-administered urocortin-2, a selective corticotropin-releasing factor receptor 2 (CRF(2)) agonist, on rat anxiety-like behaviour, the expression of c-Fos and CRF, and plasma corticosterone levels was examined in the present study. When applied to animals exposed to the conditioned fear-induced context, urocortin-2 enhanced a conditioned freezing fear response. Urocortin-2 also significantly decreased rat exploratory activity in the open field test. Exogenous urocortin-2 increased the conditioned fear-induced expression of c-Fos in the central amygdala (CeA), and parvocellular neurons of the paraventricular hypothalamic nucleus (pPVN), and revealed the effect of conditioned fear in the medial amygdala (MeA). In the fear-conditioned animals, immunocytochemistry showed an increase in the density of CRF-related immunoreactive complexes in the lateral septum (LS), 35min after urocortin-2 administration and 10min after the conditioned fear test, compared with saline-pretreated fear-conditioned animals. These data suggest a role of urocortin-2 in the behavioural and immunocytochemical responses to stress, in which it strengthens the measures of anxiety-like responses.

Novel neuroprotective strategies in ischemic retinal lesions.

Retinal ischemia can be effectively modeled by permanent bilateral common carotid artery occlusion, which leads to chronic hypoperfusion-induced degeneration in the entire rat retina. The complex pathways leading to retinal cell death offer a complex approach of neuroprotective strategies. In the present review we summarize recent findings with different neuroprotective candidate molecules. We describe the protective effects of intravitreal treatment with: (i) urocortin 2; (ii) a mitochondrial ATP-sensitive K(+) channel opener, diazoxide; (iii) a neurotrophic factor, pituitary adenylate cyclase activating polypeptide; and (iv) a novel poly(ADP-ribose) polymerase inhibitor (HO3089). The retinoprotective effects are demonstrated with morphological description and effects on apoptotic pathways using molecular biological techniques.

Urocortin 1 improves renal function in rats with streptozotocin-induced diabetes by inhibiting overproduction of TGF-beta 1 and VEGF.

BACKGROUND AND PURPOSE: Renal function can be assessed by measuring albuminuria and glomerular filtration rate, and the latter is often estimated by creatinine clearance rate (Ccr). Transforming growth factor-beta1 (TGF-beta1) and vascular endothelial growth factor (VEGF) are two important factors involved in the progressive loss of renal function in diabetic nephropathy (DN), especially in terms of albuminuria. We investigated the effect of urocortin 1 on renal function of rats with DN and the mechanisms involved. EXPERIMENTAL APPROACH: A modified rat model of DN (multiple injections of low-dose streptozotocin and complete Freund's adjuvant) and a rat mesangial cell line were used. Albuminuria and Ccr were measured or calculated. Expression and secretion of TGF-beta1 and VEGF were measured by immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR) or enzyme-linked immunosorbent assay (R&D System, Inc., Minneapolis, MA, USA). Urocortin 1 and astressin [a non-selective antagonist of corticotrophin-releasing factor (CRF) receptors] were given as daily injections for 8 weeks. KEY RESULTS: Treatment of DN rats with urocortin 1 decreased albuminuria, renal weight and overexpression of TGF-beta1 and VEGF but enhanced Ccr. Furthermore, VEGF mRNA was increased in kidneys of DN rats, and this increase was reduced by treatment with urocortin 1. The secretion of VEGF induced by TGF-beta1 in mesangial cells was inhibited by urocortin 1 pretreatment. Astressin given with urocortin 1 prevented most of the effects of urocortin 1, in our models, in vivo or in vitro. CONCLUSION AND IMPLICATIONS: Our results strongly suggest that urocortin 1 improved renal function in rats with DN by inhibiting the overproduction of TGF-beta1 and VEGF.

Neuropeptides rescue mice from lethal sepsis by down-regulating secretion of the late-acting inflammatory mediator high mobility group box 1.

Originally described as a nuclear protein that bends DNA, the high mobility group box 1 protein (HMGB1) has recently emerged as a necessary and sufficient late mediator of severe sepsis. HMGB1 is therefore a molecular target that provides a wide window for clinical intervention in sepsis. Vasoactive intestinal peptide (VIP) and urocortin are two well known anti-inflammatory neuropeptides that protect against several immune disorders by regulating a wide panel of inflammatory mediators. In this study, we demonstrate the therapeutic effect of VIP and urocortin in various models of established sepsis: both agents reduced lethality induced by cecal ligation and puncture or by injection of live Escherichia coli. The therapeutic effect of VIP and urocortin was accompanied by a decrease in systemic levels of HMGB1. In addition, administration of recombinant HMGB1 completely reversed the protective effect of VIP and urocortin in experimental sepsis. In vitro and ex vivo studies show that both VIP and urocortin down-regulate translocation of HMGB1 from the nucleus to the cytoplasm and its subsequent secretion by activated macrophages, suggesting that macrophages are major targets in the inhibitory activity of these neuropeptides. To our knowledge, VIP and urocortin are the first endogenous inhibitors of HMGB1 secretion shown to improve sepsis survival in a clinically relevant time frame.

Urocortin's inhibition of tumor growth and angiogenesis in hepatocellular carcinoma via corticotrophin-releasing factor receptor 2.

Urocortin (UCN) functions via corticotrophin-releasing factor receptors (CRFRs), CRFR1 & 2. CRFR2 is reported to be a tonic suppressor of vascularization, implying its role in tumor angiogenesis. Here, it was found that UCN inhibited the growth of hepatocellular carcinoma (HCC) and reduced tumor microvessel density in nude mice. Hepatoma cells didn't express CRFRs whereas vessels expressed CRFRs, mainly CRFR2. In vitro three-dimensional culture assay showed UCN inhibited angiogenesis, this effect was abolished by CRFR2 antagonist, anti-sauvagine-30, demonstrating involvement of CRFR2. Furthermore, UCN inhibited the proliferation and promoted the apoptosis of endothelial cells and down-regulated VEGF expression in vivo via CRFR2.