scholarly journals Natriuretic Peptide Expression and Function in GH3 Somatolactotropes and Feline Somatotrope Pituitary Tumours

2021 ◽  
Vol 22 (3) ◽  
pp. 1076
Author(s):  
Samantha M. Mirczuk ◽  
Christopher J. Scudder ◽  
Jordan E. Read ◽  
Victoria J. Crossley ◽  
Jacob T. Regan ◽  
...  
Keyword(s):  
Natriuretic Peptide ◽  
Natriuretic Peptides ◽  
Tumour Volume ◽  
Pituitary Tumour ◽  
Gh3 Cells ◽  
Loss Of Function ◽  
Pituitary Tumours ◽  
Human Pituitary ◽  
Oestrogen Treatment ◽  
And Function

Patients harbouring mutations in genes encoding C-type natriuretic peptide (CNP; NPPC) or its receptor guanylyl cyclase B (GC-B, NPR2) suffer from severe growth phenotypes; loss-of-function mutations cause achondroplasia, whereas gain-of-function mutations cause skeletal overgrowth. Although most of the effects of CNP/GC-B on growth are mediated directly on bone, evidence suggests the natriuretic peptides may also affect anterior pituitary control of growth. Our previous studies described the expression of NPPC and NPR2 in a range of human pituitary tumours, normal human pituitary, and normal fetal human pituitary. However, the natriuretic peptide system in somatotropes has not been extensively explored. Here, we examine the expression and function of the CNP/GC-B system in rat GH3 somatolactotrope cell line and pituitary tumours from a cohort of feline hypersomatotropism (HST; acromegaly) patients. Using multiplex RT-qPCR, all three natriuretic peptides and their receptors were detected in GH3 cells. The expression of Nppc was significantly enhanced following treatment with either 100 nM TRH or 10 µM forskolin, yet only Npr1 expression was sensitive to forskolin stimulation; the effects of forskolin and TRH on Nppc expression were PKA- and MAPK-dependent, respectively. CNP stimulation of GH3 somatolactotropes significantly inhibited Esr1, Insr and Lepr expression, but dramatically enhanced cFos expression at the same time point. Oestrogen treatment significantly enhanced expression of Nppa, Nppc, Npr1, and Npr2 in GH3 somatolactotropes, but inhibited CNP-stimulated cGMP accumulation. Finally, transcripts for all three natriuretic peptides and receptors were expressed in feline pituitary tumours from patients with HST. NPPC expression was negatively correlated with pituitary tumour volume and SSTR5 expression, but positively correlated with D2R and GHR expression. Collectively, these data provide mechanisms that control expression and function of CNP in somatolactotrope cells, and identify putative transcriptional targets for CNP action in somatotropes.

scholarly journals Correlation of VEGF production with IL1α and IL6 secretion by human pituitary adenoma cells

2005 ◽  
Vol 152 (2) ◽  
pp. 293-300 ◽  
Author(s):  
S A Borg ◽  
K E Kerry ◽  
J A Royds ◽  
R D Battersby ◽  
T H Jones
Keyword(s):  
Pituitary Adenoma ◽  
Tumour Volume ◽  
Pituitary Tumour ◽  
Angiogenic Factor ◽  
Tumour Cell Line ◽  
Pituitary Tumours ◽  
Human Pituitary ◽  
Human Pituitary Adenoma ◽  
Invasive Status ◽  
Significant Addition

Objectives: Vascular endothelial growth factor (VEGF) is considered to be the most important angiogenic factor involved in the neovascularisation of solid tumours. Regulatory molecules include cytokines and growth factors. Interleukin (IL)1 and IL6 have both been shown to regulate VEGF levels in a variety of tissues. The role of cytokines in the pathogenesis of pituitary tumours remains unclear. We have examined the expression of VEGF and its relationships with IL1 and IL6 in the human pituitary tumour cell line HP75 and a series of human pituitary tumours. We have also looked at the relationship of tumour volume and invasive status to VEGF secretion. Methods: Surgically resected tumours were routinely cultured in single-cell suspension at 200 K/well (standard unit for culture of dispersed primary pituitary adenoma cells). We measured VEGF, IL1α and IL6 levels by ELISA. Tumour volume and invasion grade were assessed by preoperative magnetic resonance imaging. Results: VEGF was detected in conditioned medium of HP75 cells (900±52 pg/ml) and in 82% of tumours tested (range 26–16 464 pg/ml). Tumour volume and secretion of VEGF were significantly associated with levels of IL6 (volume, P = 0.056; VEGF, P < 0.001 (P values based on Spearman’s test)) and IL1α produced (volume, P < 0.005; VEGF, P < 0.001). Invasive tumours showed a higher basal secretion of VEGF that that of the non-invasive type; however, this difference was not significant. Addition of exogenous IL1α, but not IL6, significantly increased VEGF production. Conclusions: The significant associations between VEGF and the levels of IL6 and IL1α suggest an important role for these cytokines in the development of these tumours.

A critical reappraisal of MIB-1 labelling index significance in a large series of pituitary tumours: secreting versus non-secreting adenomas.

2002 ◽  
pp. 103-113 ◽  
Author(s):  
M L Jaffrain-Rea ◽  
D Di Stefano ◽  
G Minniti ◽  
V Esposito ◽  
A Bultrini ◽  
...  
Keyword(s):  
Operative Treatment ◽  
Hormone Secretion ◽  
Tumour Volume ◽  
Pituitary Tumour ◽  
Labelling Index ◽  
Pituitary Tumours ◽  
Life Threatening ◽  
The Mean ◽  
Monoclonal Antibody Mib 1 ◽  
Mib 1

Pituitary tumours are usually benign neoplasia, but may have a locally aggressive or malignant evolution. This study aimed to identify factors which mostly influence their proliferative activity, in order to clarify its value for clinical and research purposes. The proliferative index was determined in a prospective series of 132 pituitary tumours as the percentage of monoclonal antibody MIB-1-immunopositive cells and referred to as the MIB-1 labelling index (LI). Its distribution was analysed according to both univariate and multivariate models. A life-threatening pituitary tumour is presented separately. The mean LI was 1.24+/-1.59%, with significant differences between clinically secreting (CS) and clinically non-secreting (CNS) adenomas. In CS adenomas (n=65), LI was highly variable and markedly influenced by pre-operative pharmacological treatment (0.80+/-1.03 vs 2.06+/-2.39% in treated vs untreated cases, P=0.009); it decreased with patient's age (P=0.025, r=0.28) and increased with tumour volume and invasiveness. The influence of pre-operative treatment and macroscopic features on LI in this group was confirmed by multivariate analysis. In CNS adenomas (n=67), LI distribution was less variable than in CS adenomas (P<0.0001), it was age-independent and correlations with tumour volume, invasiveness or recurrence did not reach significance. In a rapidly growing parasellar tumour, the mean LI was 24% at first surgery and exceeded 50% at second surgery performed 4 months later. LI should be interpreted according to hormone secretion and pre-operative treatment. Unusually high LI values deserve particular attention.

Abstract 4579: Endogenous Brain Natriuretic Peptide (BNP) Protects Against Apoptosis of Ischemic Human Astrocytes in an Autocrine Fashion

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Chisato Katoh ◽  
Hirofumi Tomita ◽  
Norifumi Metoki ◽  
Genta Saitoh ◽  
Tomohiro Osanai ◽  
...  
Keyword(s):  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Early Stage ◽  
Infarct Volume ◽  
Fold Increase ◽  
Brain Diseases ◽  
Loss Of Function ◽  
Human Astrocytes ◽  
Apoptotic Effect ◽  
And Function

The plasma brain natriuretic peptide (BNP) level is increased in the acute phase of human stroke, but its source and function are unclear. Recently, we showed that the BNP level was higher in atherothrombotic cerebral infarction (69.1±9.4 pg/ml) than in control subjects (31.1±5.4 pg/ml), and that the BNP level in ischemic stroke was positively correlated with the NIH Stroke Scale (r=0.41, p<0.05) and infarct volume (r=0.34, p<0.05). Astrocytes provide metabolic and trophic support to neurons and modulate synaptic activities. At the early stage of brain ischemia, astrocytes are swollen, and their damage may compromise postischemic neuronal survival. We tested the hypothesis that human astrocytes produce BNP under hypoxia, and this endogenous BNP protects against apoptosis in an autocrine fashion. The human astrocyte cell line, U373MG, was exposed to hypoxia (O 2 ≤1%) for 24 hours. The ratio of BNP to GAPDH mRNA was increased by 7.7±.0 fold after 12-hour hypoxia and further increased by 8.6±1.6 fold after 24-hour hypoxia compared with that in 3-hour normoxia (both, p<0.01). The protein expression assessed by Western blot was increased by 2.0±0.4 fold at 24 hours (n=5, p<0.05). Tyrosine phosphorylation of c-Src was observed by 2.0±0.2-fold increase at 30 minutes. These responses to hypoxia were all blocked by pretreatment with PP1 at 50μM, an inhibitor of c-Src. Apoptosis was measured by detecting caspase activation by flow cytometry, and it was increased by 2.5±0.1 fold after 24-hour hypoxia compared with that in normoxia. To investigate the role of up-regulated BNP in apoptosis, we performed the loss of function test by transfecting a specific siRNA for NPPB that suppressed BNP by more than 80%. The activity of caspases in the BNP knockdown cells was increased by 3.2±0.2 fold after 24-hour hypoxia compared with that in normoxia (n=5, p<0.001), and it was greater than that in the cells transfected with non-targeting siRNA. These results indicate that hypoxia increases BNP gene expression through the c-Src-dependent signaling cascade in the human astrocytes. Endogenous BNP shows brain protection via the anti-apoptotic effect. BNP may be useful in the treatment of ischemic brain diseases.

scholarly journals Cardiovascular Pleiotropic Effects of Natriuretic Peptides

2019 ◽  
Vol 20 (16) ◽  
pp. 3874 ◽  
Author(s):  
Forte ◽  
Madonna ◽  
Schiavon ◽  
Valenti ◽  
Versaci ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Natriuretic Peptide ◽  
Natriuretic Peptides ◽  
Vascular System ◽  
Ischemia Reperfusion ◽  
Pressure Overload ◽  
Pleiotropic Effects ◽  
Current Evidence ◽  
Loss Of Function ◽  
Cardiac Phenotype

Atrial natriuretic peptide (ANP) is a cardiac hormone belonging to the family of natriuretic peptides (NPs). ANP exerts diuretic, natriuretic, and vasodilatory effects that contribute to maintain water–salt balance and regulate blood pressure. Besides these systemic properties, ANP displays important pleiotropic effects in the heart and in the vascular system that are independent of blood pressure regulation. These functions occur through autocrine and paracrine mechanisms. Previous works examining the cardiac phenotype of loss-of-function mouse models of ANP signaling showed that both mice with gene deletion of ANP or its receptor natriuretic peptide receptor A (NPR-A) developed cardiac hypertrophy and dysfunction in response to pressure overload and chronic ischemic remodeling. Conversely, ANP administration has been shown to improve cardiac function in response to remodeling and reduces ischemia-reperfusion (I/R) injury. ANP also acts as a pro-angiogenetic, anti-inflammatory, and anti-atherosclerotic factor in the vascular system. Pleiotropic effects regarding brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) were also reported. In this review, we discuss the current evidence underlying the pleiotropic effects of NPs, underlying their importance in cardiovascular homeostasis.

Dysregulation of iodothyronine deiodinase enzyme expression and function in human pituitary tumours

2002 ◽  
Vol 56 (6) ◽  
pp. 735-743 ◽  
Author(s):  
L. A. Tannahill ◽  
T. J. Visser ◽  
C. J. McCabe ◽  
S. Kachilele ◽  
K. Boelaert ◽  
...  
Keyword(s):  
Enzyme Expression ◽  
Pituitary Tumours ◽  
Human Pituitary ◽  
Iodothyronine Deiodinase ◽  
And Function

scholarly journals Pituitary tumours: findings from whole genome analyses

2006 ◽  
Vol 13 (3) ◽  
pp. 707-716 ◽  
Author(s):  
W E Farrell
Keyword(s):  
Animal Models ◽  
New Technologies ◽  
Pituitary Tumour ◽  
Comparative Genomic ◽  
Whole Genome ◽  
Pituitary Tumours ◽  
Novel Genes ◽  
Human Pituitary ◽  
Genome Wide ◽  
Pituitary Tumorigenesis

Pituitary tumours are common intracranial neoplasms that cause significant morbidity through mass effects and/or the inappropriate secretion of pituitary hormones. Despite a considerable literature detailing potential pathogenic changes in these tumours, their aetiology remains largely unresolved. Recent studies have employed genome-wide profiling towards the identification of novel genes and pathways that are inappropriately expressed or regulated in this tumour type. The techniques employed vary in their complexity and interpretation; however, many of the findings from these types of studies have identified novel genes with potential and, in some cases, proven roles in pituitary tumorigenesis. These studies include comparative genomic hybridization, whole genome-wide allelotyping and methodologies for identification of novel genes associated with epigenetic silencing. In addition, differential display methodologies have been instrumental in the identification of transcripts inappropriately expressed including, pituitary tumour transforming gene, growth arrest and DNA damage-inducible protein (GADD)45γ and a maternal expressed gene 3 isoform, which in some cases have proven roles in pituitary tumorigenesis. Although few studies of whole genome transcript analysis, as determined by microarray or gene-chip technologies, are reported, these studies of human pituitary, in some cases combined with proteomics, are yielding useful data. In addition, these types of investigation have been applied to several animal models of pituitary tumorigenesis, and in these cases novel genes are highlighted as showing significant change. The identification of the initiating events responsible for the transformation of a normal pituitary cell into one with unrestrained proliferative capacity has so far eluded us. No doubt, these new technologies allowing an essentially unbiased genome-wide analysis, perhaps in combination with animal models that display a preceding hyperplasia, will allow us to identify genes critical to tumour evolution and progression.

scholarly journals Temozolomide treatment of a pituitary carcinoma and two pituitary macroadenomas resistant to conventional therapy

2009 ◽  
Vol 161 (4) ◽  
pp. 631-637 ◽  
Author(s):  
C Hagen ◽  
H D Schroeder ◽  
S Hansen ◽  
C Hagen ◽  
M Andersen
Keyword(s):  
Dna Methyltransferase ◽  
English Literature ◽  
Tumour Size ◽  
Tumour Volume ◽  
Pituitary Tumour ◽  
Tumour Mass ◽  
Pituitary Tumours ◽  
Hormone Levels ◽  
Mass Effects ◽  
Methylguanine Dna Methyltransferase

ObjectiveAggressive pituitary tumours may be difficult to treat. Temozolomide (TMZ) is an alkylating cytostaticum. In a small number of cases, TMZ therapy has been reported to reduce pituitary tumour size and hormone hypersecretion.DesignWe present three patients with pituitary tumours treated with TMZ. One tumour was initially a macroprolactinoma that developed into a mixed GH- and prolactin-secreting carcinoma (patient A). To our knowledge, this is the first published in English literature. Two adenomas, a macroprolactinoma (patient B) and a clinically non-functioning pituitary adenoma (patient C), were highly invasive. The three patients suffered from extensive tumour mass effects, and all tumours were resistant to conventional treatment.MethodTMZ, 150–200 mg/m2 of body surface area was administered orally for 5 days during each 28-day cycle.ResultDuring TMZ therapy, tumour sizes were significantly reduced, hormone levels normalized and symptoms of mass effects decreased in all three cases. The carcinoma was treated from 2004 to 2006 (23 months). Three years after the terminating treatment, the tumour has not regrown and hormone levels are normalized. Immunohistochemical staining for methylguanine DNA methyltransferase (MGMT) was negative in two patients (A and B), and in one patient (C) a few nuclei stained positive.ConclusionTMZ therapy significantly decreased tumour volume, hormone hypersecretion and symptoms in all three patients, corresponding to the pathological findings regarding MGMT. TMZ therapy may be a new option for the treatment of resistant pituitary adenomas.

Association between natriuretic peptides and left atrial structural and functional properties in atrial fibrillation following catheter ablation

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
F.J Olsen ◽  
S Darkner ◽  
J.P Gotze ◽  
X Chen ◽  
K Henningsen ◽  
...  
Keyword(s):  
Catheter Ablation ◽  
Natriuretic Peptide ◽  
Natriuretic Peptides ◽  
Left Atrial ◽  
Left Ventricular ◽  
Structure And Function ◽  
Funding Source ◽  
And Function ◽  
The Relationship

Abstract Background Atrial natriuretic peptides (ANP) and brain natriuretic peptides (BNP) are acutely released from the atrial myocytes upon increased mechanical distension of the atria. The relationship between imaging measures of left atrial (LA) structure and function and natriuretic peptides following catheter ablation (CA) have not been clearly delineated. Purpose To characterize the relationship between LA structure and function and natriuretic peptides. Methods We performed an echocardiographic substudy of a randomized trial of AF patients scheduled for CA. Echocardiographic measurements included: LA volume at end-systole (LAVi), at end-diastole (LAEDVi), emptying fraction (LAEF), LA reservoir strain (LAs), and global longitudinal strain (GLS). Patients were stratified by tertiles of mid-regional proANP (MR-proANP) concentrations in circulation (&lt;92 pmol/l, 92–146 pmol/l, &gt;146 pmol/l), and NT-proBNP (&lt;10pmol/l, 10–38 pmol/l, &gt;38 pmol/l). Linear regressions were performed to compare baseline echocardiographic measures to natriuretic peptide concentrations at baseline, 1 month, 3 months and 6 months of follow-up. MR-proANP and NT-proBNP were logarithm transformed in these analyses. Multivariable adjustments were made for: age, gender, AF subtype, AF burden, rhythm during echocardiogram, rhythm at study visit for blood sampling, time known with AF, beta-blocker use, and CHA-2DS2-VASc score. Results We included 101 patients with AF. The mean age was 58 years, 82% were men, 46% had persistent AF. Increasing tertiles of MR-proANP at baseline were associated with abnormal LA size and function (3rd vs 1st tertile: LAVi: 42mL/m2 vs 32mL/m2; LAEDVi: 31mL/m2 vs 20mL/m2; LAEF: 38% vs 26%; LAs: 27% vs 19%; GLS: −18% vs −14%) whereas both LA and left ventricular measures were associated with increasing NT-proBNP concentrations at baseline. After multivariable adjustments, only LA volumes and LAEF remained significantly associated with MR-proANP, whereas only LA volumes and GLS remained significantly associated with NT-proBNP. At follow-up, impaired LA function associated with persistently elevated concentrations, which was not the case for LAVi (figure). Conclusion MR-proANP reflects LA dysfunction better than NT-proBNP. Measures of LA function rather than LAVi associates with persistently elevated natriuretic peptide concentrationsw, which may indicate that functional measures are more closely associated with evidence of LA myocardial stretch than LAVi. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): The Danish Heart Foundation

scholarly journals Curcumin suppresses HIF1A synthesis and VEGFA release in pituitary adenomas

2012 ◽  
Vol 214 (3) ◽  
pp. 389-398 ◽  
Author(s):  
B Shan ◽  
C Schaaf ◽  
A Schmidt ◽  
K Lucia ◽  
M Buchfelder ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Cell Cultures ◽  
Curcuma Longa ◽  
Pituitary Tumour ◽  
Tumour Cells ◽  
Gh3 Cells ◽  
Mrna Synthesis ◽  
Human Pituitary ◽  
Human Pituitary Adenoma ◽  
Adenoma Cell

Curcumin (diferuloylmethane), a polyphenolic compound derived from the spice plantCurcuma longa, displays multiple actions on solid tumours including anti-angiogenic effects. Here we have studied in rodent and human pituitary tumour cells the influence of curcumin on the production of hypoxia inducible factor 1α (HIF1A) and vascular endothelial growth factor A (VEGFA), two key components involved in tumour neovascularisation through angiogenesis. Curcumin dose-dependently inhibited basal VEGFA secretion in corticotroph AtT20 mouse and lactosomatotroph GH3 rat pituitary tumour cells as well as in all human pituitary adenoma cell cultures (n=32) studied. Under hypoxia-mimicking conditions (CoCl2treatment) in AtT20 and GH3 cells as well as in all human pituitary adenoma cell cultures (n=8) studied, curcumin strongly suppressed the induction of mRNA synthesis and protein production of HIF1A, the regulated subunit of the hypoxia-induced transcription factor HIF1. Curcumin also blocked hypoxia-induced mRNA synthesis and secretion of VEGFA in GH3 cells and in all human pituitary adenoma cell cultures investigated (n=18). Thus, curcumin may inhibit pituitary adenoma progression not only through previously demonstrated anti-proliferative and pro-apoptotic actions but also by its suppressive effects on pituitary tumour neovascularisation.

Role of cardiac natriuretic peptides in seawater adaptation of medaka embryos as revealed by loss-of-function analysis

2013 ◽  
Vol 304 (6) ◽  
pp. R423-R434 ◽  
Author(s):  
Hiroshi Miyanishi ◽  
Kataaki Okubo ◽  
Toyoji Kaneko ◽  
Yoshio Takei
Keyword(s):  
Blood Flow ◽  
Natriuretic Peptide ◽  
Natriuretic Peptides ◽  
Body Fluid ◽  
Blood Circulation ◽  
Function Analysis ◽  
Water Production ◽  
Loss Of Function ◽  
Seawater Adaptation ◽  
Cardiac Natriuretic Peptides

Cardiac natriuretic peptides (atrial natriuretic peptide, ANP; b-type natriuretic peptide, BNP; ventricular natriuretic peptide, VNP) and their direct ancestor C-type natriuretic peptide 3 (CNP3) exert potent osmoregulatory actions in fish. However, very little is known about their roles in embryonic osmoregulation. In this study, we performed loss-of-function analysis using euryhaline medaka ( Oryzias latipes), which has lost ANP and VNP during evolution and thus possesses only BNP and CNP3. We found that the maintenance of whole-body osmolality in seawater embryos was impaired by the knockdown of BNP+OLGC7 (BNP receptor) or CNP3 alone from 1 day postfertilization, and the CNP3 knockdown was accompanied by greater water loss. The impaired osmoregulation in the knockdown embryos was not due to the suppressed expression of major transporters for NaCl excretion via ionocytes or of key enzyme genes for metabolic water production, but to the impaired blood circulation to the yolk-sac membrane caused by abnormal heart development. We detected a strong positive correlation between impaired blood circulation and increased body fluid osmolality and pharmacological blockade of blood flow increased body fluid osmolality in seawater embryos. We also found that the exaggerated water loss in CNP3 knockdown embryos is related to the failure to suppress aquaporin (AQP3, AQP4, and AQP9) gene expression. These results show that CNP3 decrease water permeability of body surfaces and that both BNP and CNP3 ensure sufficient blood flow to the yolk-sac membrane for efficient salt excretion by ionocytes and sufficient water production by yolk metabolism to promote seawater adaptation during early development in medaka.

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