scholarly journals Local IGF Bioactivity Associates with High PAPP-A Activity in the Pericardial Cavity of Cardiovascular Disease Patients

2020 ◽  
Vol 105 (11) ◽  
Author(s):  
Rikke Hjortebjerg ◽  
Lars Melholt Rasmussen ◽  
Mette Faurholdt Gude ◽  
Akhmadjon Irmukhamedov ◽  
Lars P Riber ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Protein A ◽  
Pericardial Fluid ◽  
Pericardial Cavity ◽  
Protein Levels ◽  
Igf I ◽  
Igf Binding ◽  
A Cell ◽  
Stanniocalcin 2 ◽  
Fluid Levels

Abstract Objective Pregnancy-associated plasma protein-A (PAPP-A) has been suggested as a proatherogenic enzyme by its ability to locally increase insulin-like growth factor (IGF) activity through proteolytic cleavage of IGF binding protein-4 (IGFBP-4). Recently, stanniocalcin-2 (STC2) was discovered as an inhibitor of PAPP-A. This study aimed to investigate IGFBP-4, PAPP-A, and STC2 as local regulators of IGF bioactivity in the cardiac microenvironment by comparing levels in the pericardial fluid with those in the circulation of patients with cardiovascular disease. Methods Plasma and pericardial fluid were obtained from 39 patients undergoing elective cardiothoracic surgery, hereof 15 patients with type 2 diabetes. Concentrations of IGF-I, intact and fragmented IGFBP-4, PAPP-A, and STC2 were determined by immunoassays and IGF bioactivity by a cell-based assay. Results In pericardial fluid, the concentrations of total IGF-I, intact IGFBP-4, and STC2 were 72 ± 10%, 91 ± 5%, and 40 ± 24% lower than in plasma, while PAPP-A was 15 times more concentrated. The levels of the 2 IGFBP-4 fragments generated by PAPP-A and reflecting PAPP-A activity were elevated by more than 25%. IGF bioactivity was 62 ± 81% higher in the pericardial fluid than plasma. Moreover, pericardial fluid levels of both IGFBP-4 fragments correlated with the concentration of PAPP-A and with the bioactivity of IGF. All protein levels were similar in pericardial fluid from nondiabetic and diabetic subjects. Conclusions PAPP-A increases IGF bioactivity by cleavage of IGFBP-4 in the pericardial cavity of cardiovascular disease patients. This study provides evidence for a distinct local activity of the IGF system, which may promote cardiac dysfunction and coronary atherosclerosis.

scholarly journals Insulin-Like Growth Factor Bioactivity, Stanniocalcin-2, Pregnancy-Associated Plasma Protein-A, and IGF-Binding Protein-4 in Pleural Fluid and Serum From Patients With Pulmonary Disease

2017 ◽  
Vol 102 (9) ◽  
pp. 3526-3534 ◽  
Author(s):  
Ulrick Skipper Espelund ◽  
Mette Bjerre ◽  
Rikke Hjortebjerg ◽  
Torben Riis Rasmussen ◽  
Anders Lundby ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pleural Fluid ◽  
Plasma Protein ◽  
Binding Protein ◽  
Protein A ◽  
Insulin Like Growth Factor ◽  
Igf System ◽  
Igf Binding ◽  
Stanniocalcin 2 ◽  
Igf Binding Protein

Abstract Context Members of the insulin-like growth factor (IGF) system are primarily produced in the liver and secreted into the circulation, but they are also produced, recruited, and activated locally in tissues. Objective To compare activity and concentrations of IGF system components in pleural fluid and blood. Design Pathological pleural fluid, secondary to lung cancer or nonmalignant disease, and matching blood samples were collected from 24 patients ages 66.7 to 81.9 years. Methods IGF-related proteins and cytokine levels were measured by immunoassays or immunoblotting. Bioactive IGF was measured by an IGF-1 receptor phosphorylation assay. Results Total IGF-1 concentration did not differ between the compartments, but concentrations of free IGF-1 and bioactive IGF were more than threefold higher in pleural fluid than in corresponding serum samples (P = 0.0004), regardless of etiology. Median pregnancy-associated plasma protein-A (PAPP-A) and interleukin (IL)-6 levels were increased 47-fold and 143-fold, respectively, in pleural fluid compared with plasma (P < 0.0001). PAPP-A and IL-6 concentrations correlated positively (r = 0.46; P = 0.02). In pleural fluid, levels of PAPP-A–generated IGF binding protein-4 fragments correlated inversely with that of stanniocalcin-2 (r ≤ −0.42; P ≤ 0.05), a PAPP-A inhibitor; such correlations were absent in plasma. Conclusion Pathological pleural fluid is characterized by increased in vitro IGF bioactivity and elevated concentrations of PAPP-A, an IGF-activating proteinase. Thus, the tissue activity of the IGF system may differ substantially from that of the circulating IGF system. The correlation between IL-6 and PAPP-A indicates that inflammation plays a role in promoting local tissue IGF activity.

Depot-specific and GH-dependent regulation of IGF binding protein-4, pregnancy-associated plasma protein-A, and stanniocalcin-2 in murine adipose tissue

2018 ◽  
Vol 39 ◽  
pp. 54-61 ◽  
Author(s):  
Rikke Hjortebjerg ◽  
Darlene E. Berryman ◽  
Ross Comisford ◽  
Edward O. List ◽  
Claus Oxvig ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Plasma Protein ◽  
Binding Protein ◽  
Protein A ◽  
Igf Binding ◽  
Stanniocalcin 2 ◽  
Igf Binding Protein

scholarly journals The Somatomedin Hypothesis: 2001

2001 ◽  
Vol 22 (1) ◽  
pp. 53-74 ◽  
Author(s):  
Derek Le Roith ◽  
Carolyn Bondy ◽  
Shoshana Yakar ◽  
Jun-Li Liu ◽  
Andrew Butler
Keyword(s):  
Growth And Development ◽  
Gene Deletion ◽  
Somatic Growth ◽  
Postnatal Growth ◽  
Protein Levels ◽  
Factor I ◽  
Igf I ◽  
Igf Binding ◽  
Igf Binding Protein

Abstract Since the original somatomedin hypothesis was conceived, a number of important discoveries have allowed investigators to modify the concept. Originally somatic growth was thought to be controlled by pituitary GH and mediated by circulating insulin-like growth factor-I (IGF-I, somatomedin C) expressed exclusively by the liver. With the discovery that IGF-I is produced by most, if not all, tissues, the role of autocrine/paracrine IGF-I vs. the circulating form has been hotly debated. Recent experiments using transgenic and gene-deletion technologies have attempted to answer these questions. In the liver-specific igf-1 gene-deleted mouse model, postnatal growth and development are normal despite the marked reduction in circulating IGF-I and IGF-binding protein levels; free IGF-I levels are normal. Thus, the normal postnatal growth and development in these animals may be due to normal free IGF-I levels (from as yet unidentified sources), although the role of autocrine/paracrine IGF-I has yet to be determined.

Regulation of IGF-binding protein-6 by dexamethasone and IGFs in PC12 rat phaeochromocytoma cells

1997 ◽  
Vol 155 (2) ◽  
pp. 225-232 ◽  
Author(s):  
LA Bach ◽  
KS Leeding ◽  
SL Leng
Keyword(s):  
Pc12 Cells ◽  
Binding Protein ◽  
Mrna Level ◽  
Cell Number ◽  
Mrna Levels ◽  
Protein Levels ◽  
Igf Receptors ◽  
Igf Binding ◽  
A Cell ◽  
Igf Binding Protein

PC12 rat phaeochromocytoma cells are widely used as a model of neuronal differentiation. They express IGF receptors and are responsive to IGFs. The main IGF-binding protein synthesized by these cells is IGFBP-6. Glucocorticoids induce differentiation of PC12 cells towards a chromaffin phenotype. The effect of dexamethasone on IGFBP-6 levels was therefore studied. Dexamethasone (500 nM) decreased IGFBP-6 protein in conditioned media and mRNA levels to 61 +/- 5% (P < 0.0001) and 34 +/- 14% (P = 0.03) of control levels respectively. Incubation of PC12 cells with IGF-II (100 ng/ml) for 72 h increased IGFBP-6 protein levels in media to 217 +/- 19% of control (P < 0.0001). IGFBP-6 mRNA levels, however, were unchanged. IGF-I had similar effects on IGFBP-6 protein and mRNA levels. IGFs increased cell number by 50-60%, but this was insufficient to explain the increases in protein levels. IGFBP-6 was not released from a cell-associated reservoir or protected from proteolysis by IGFs, excluding these post-translational mechanisms as explanations for the IGF effects on IGFBP-6 levels. The effects of IGF-II and dexamethasone on IGFBP-6 levels were independent. These results indicated that (1) dexamethasone decrease IGFBP-6 at the mRNA level, and (2) IGFs stimulate IGFBP-6 levels by a post-transcriptional mechanism.

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