Circulating Neuregulin-1 and Chronic Heart Failure with Preserved Ejection

Chronic heart failure (CHF) with preserved ejection fraction (CHFpEF) is an unsolved, socially relevant challenge since it is associated with a high level of morbidity and mortality. Early markers for this pathology are unavailable, and therapeutic approaches are undeveloped. This necessitates extensive studying the mechanisms of CHFpEF to identify therapeutic targets. According to current notions, systemic inflammation and endothelial dysfunction play an important role in the pathogenesis of CHFpEF. These processes induce the development of myocardial fibrosis and impairment of cardiomyocyte relaxation, thereby resulting in diastolic dysfunction and increased left ventricular (LV) filling pressure. Neuregulin-1 (NRG-1) is a paracrine growth factor and a natural agonist of ErbB receptor family synthesized in the endothelium of coronary microvessels. The NRG-1 / ErbB4 system of the heart is activated at early stages of CHFpEF to enhance the cardiomyocyte resistance to oxidative stress. Preclinical and clinical (phases II and III) studies have shown that the recombinant NRG-1 therapy results in improvement of myocardial contractility and in LV reverse remodeling. Results of recent studies suggest possible anti-inflammatory and antifibrotic effects of NRG-1, which warrants studying the activity of this system in patients with CHFpEF.

Nutrient restriction in early ovine pregnancy stimulates C-type natriuretic peptide production

C-type natriuretic peptide (CNP), a paracrine growth factor promoting vasodilation and angiogenesis, is upregulated in human and ovine pregnancy in response to vascular stress or nutrient restriction (NR) in late gestation. Postulating that maternal plasma CNP products are increased by modest NR (50% of metabolisable energy requirement) early in pregnancy, and further enhanced by litter size, we studied serial changes of maternal plasma CNP in pregnant ewes receiving a normal (NC, n = 12) or restricted (NR, n = 13) diet from Day 30 to Day 93 or 94 of gestation. Liveweight of NR ewes was 10 kg less than that of NC ewes at slaughter. Plasma CNP products increased progressively after Day 40 and were higher in NR (P < 0.05) ewes after Day 60; they were also enhanced by litter size (P < 0.01) and were positively associated with increased placental efficiency. In contrast, whereas fetal and placental weight were reduced by NR, fetal plasma CNP products (Day 93/94) were not affected. We conclude that increases in CNP during rapid placental growth are further enhanced by both increasing nutrient demands and by reduced supply, presumably as part of an adaptive response benefitting placental–fetal exchange.

Synergistic Activations ofREG IαandREG IβPromoters by IL-6 and Glucocorticoids through JAK/STAT Pathway in Human PancreaticβCells

Reg(Regenerating gene) gene was originally isolated from rat regenerating islets and its encoding protein was revealed as an autocrine/paracrine growth factor forβcells. RatReggene is activated in inflammatory conditions forβcell regeneration. In human, although five functionalREGfamily genes (REG Iα, REG Iβ, REG III, HIP/PAP, andREG IV) were isolated, their expressions inβcells under inflammatory conditions remained unclear. In this study, we found that combined addition of IL-6 and dexamethasone (Dx) inducedREG IαandREG Iβexpression in human 1.1B4βcells. Promoter assay revealed that a signal transducer and activator of transcription- (STAT-) binding site in each promoter ofREG Iα(TGCCGGGAA) andREG Iβ(TGCCAGGAA) was essential for the IL-6+Dx-induced promoter activation. A Janus kinase 2 (JAK2) inhibitor significantly inhibited the IL-6+Dx-inducedREG IαandREG Iβtranscription. Electrophoretic mobility shift assay and chromatin immunoprecipitation revealed that IL-6+Dx stimulation increased STAT3 binding to theREG Iαpromoter. Furthermore, small interfering RNA-mediated targeting of STAT3 blocked the IL-6+Dx-induced expression ofREG IαandREG Iβ. These results indicate that the expression ofREG IαandREG Iβshould be upregulated in humanβcells under inflammatory conditions through the JAK/STAT pathway.

UII and UT in grouper: cloning and effects on the transcription of hormones related to growth control

Urotensin II (UII) is a cyclic peptide that was originally extracted from the caudal neurosecretory system (CNSS) of fish. UII is well known to exhibit cardiovascular, ventilatory, and motor effects in vertebrates. Studies have reported that UII exerts mitogenic effects and can act as an autocrine/paracrine growth factor in mammals. However, similar information in fish is limited. In this study, the full-length cDNAs of UII and its receptor (UT) were cloned and characterized in the orange-spotted grouper. UII and UT were expressed ubiquitously in various tissues in grouper, and particularly high levels were observed in the CNSS, CNS, and ovary. A functional study showed that UT was coupled with intracellular Ca2+ mobilization in HEK293 cells. Studies carried out using i.p. injections of UII in grouper showed the following: i) in the hypothalamus, UII can significantly stimulate the mRNA expression of ghrh and simultaneously inhibit the mRNA expression of somatostatin 1 (ss1) and ss2 3 h after injection; ii) in the pituitary, UII also significantly induced the mRNA expression of gh 6 and 12 h after injection; and iii) in the liver, the mRNA expression levels of ghr1/ghr2 and igf1/igf2 were markedly increased 12 and 3 h after the i.p. injection of UII respectively. These results collectively indicate that the UII/UT system may play a role in the promotion of the growth of the orange-spotted grouper.

Correlation of serum interleukin-6 (IL-6) levels and clinical outcome in hormone-independent (HI) prostate cancer (PC) patients (PTS) treated with docetaxel

e16044 Background: IL-6 acts as an autocrine and paracrine growth factor in PC, linked to HI progression. We previously reported preliminary data on the correlation of serum IL-6 and D response in metastatic HI PC pts. We present here a larger group of pts tested to asses the clinical relevance of IL-6 in these pts. Methods: Pts with HIPC treated with D were prospectively tested for IL-6 levels by ELISA before D. Prostate-specific antigen (PSA) response, time to PSA progression, overall survival (OS) and PC specific survival (SpS) were analyzed. Evaluated variables were age, performance status, PSA, Gleason, number (n) of D cycles, time to HI progression, presence of visceral metastasis, n of bone metastasis, hemoglobin, lactate deshydrogenase and alkaline phosphatase. Results: Seventy-two pts were included. At the time of the analysis 5 pts had died from non-PC related causes, two from treatment toxicity and 29 (40%) from PC. Mean of age was 69 ± 7 years. Median baseline IL-6 level was 14 pg/ml (range 0.1–1100). Thirty-five pts (49 %) had IL-6 levels > 14 pg/ml. IL-6 > 14 pg/ml correlated with lower D response (13 % vs 40%, p= 0.039); lower time to PSA progression (4 months vs 6, p=0.023); lower OS (10 months vs 25, p= 0.001) and lower PC SpS (12 months vs 26, p= 0.001), in contrast to pts with IL-6 ≤ 14pg/ml. In the multivariate analysis, serum IL-6 (p=0.002), n of bone metastasis (p=0.008) and n of D cycles (p=0.002), were independent prognostic factor for OS and PC SpS. Conclusions: High serum IL-6 correlates with an adverse clinical outcome of pts with HIPC treated with D. IL-6 determination may be a potential tool to select patients for D-based or targeted therapies. FIS ( PI070388 ) No significant financial relationships to disclose.