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The insulin-like growth factors IGF-I and IGF-II—as well as their binding proteins (IGFBPs), which regulate their bioavailability—are involved in many pathological and physiological processes in cardiac tissue. Pregnancy-associated plasma protein A (PAPP-A) is a metalloprotease that preferentially cleaves IGFBP-4, releasing IGF and activating its biological activity. Previous studies have shown that PAPP-A-specific IGFBP-4 proteolysis is involved in the pathogenesis of cardiovascular diseases, such as ischemia, heart failure, and acute coronary syndrome. However, it remains unclear whether PAPP-A-specific IGFBP-4 proteolysis participates in human normal cardiomyocytes. Here, we report PAPP-A-specific IGFBP-4 proteolysis occurring in human cardiomyocytes derived from two independent induced pluripotent cell lines (hiPSC-CMs), detected both on the cell surface and in the cell secretome. PAPP-A was measured by fluoroimmune analysis (FIA) in a conditioned medium of hiPSC-CMs and was detected in concentrations of up to 4.3 ± 1.33 ng/mL and 3.8 ± 1.1 ng/mL. The level of PAPP-A-specific IGFBP-4 proteolysis was determined as the concentration of NT-IGFBP-4 proteolytic fragments using FIA for a proteolytic neo-epitope-specific assay. We showed that PAPP-A-specific IGFBP-4 proteolysis is IGF-dependent and inhibited by EDTA and 1,10-phenanthroline. Therefore, it may be concluded that PAPP-A-specific IGFBP-4 proteolysis functions in human normal cardiomyocytes, and hiPSC-CMs contain membrane-bound and secreted forms of proteolytically active PAPP-A.

One of the most vital processes of the body is the cardiovascular system’s proper operation. Physiological processes in the heart are regulated by the balance of cardioprotective and pathological mechanisms. The insulin-like growth factor system (IGF system, IGF signaling pathway) plays a pivotal role in regulating growth and development of various cells and tissues. In myocardium, the IGF system provides cardioprotective effects as well as participates in pathological processes. This review summarizes recent data on the role of IGF signaling in cardioprotection and pathogenesis of various cardiovascular diseases, as well as analyzes severity of these effects in various scenarios.

NOABSTRACTWe aimed to explore the value of serum N-terminal insulin-like growth factor-binding protein 4 (NT-IGFBP-4) in the non-invasive risk stratification of coronary heart disease and its predictive efficiency for the complexity of coronary artery lesions [assessed by Synergy between PCI with TAXUS and Cardiac Surgery (SYNTAX) and SYNTAX II scores].Subjects (180 in total) were recruited from patients treated between September 2023 and September 2024. Serum NT-IGFBP-4 level was measured. SYNTAX and SYNTAX II scores were assessed.The serum NT-IGFBP-4 level, SYNTAX score, and SYNTAX II score of the high-risk group were significantly higher than those of medium- and low-risk groups (p<0.001). The patients with more affected vessels had higher NT-IGFBP-4 levels. Univariate analysis of variance showed that NT-IGFBP-4 level was significantly different among the three risk groups (F=18.991, p<0.001), with a linear trend (p<0.001). Spearman rank correlation analysis showed that NT-IGFBP-4 level was positively correlated with the risk stratification (r=0.420, p<0.001). Multivariate logistic regression analysis showed that NT-IGFBP-4 level, SYNTAX score, and three-vessel disease were independent predictors of coronary artery lesions (p<0.05). ROC curve analysis showed that the areas under the curves of NT-IGFBP-4, SYNTAX score, and three-vessel disease were all >0.700.Serum NT-IGFBP-4 reflects the pathophysiological state of coronary heart disease when combined with the SYNTAX II scoring system. It shows a significant positive correlation with the risk of coronary heart disease and can independently predict this risk.

Vascular endothelial growth factor (VEGF) is a well‐known angiogenic factor, however its ability in promoting therapeutic angiogenesis following myocardial infarction (MI) is limited. Here, we aimed to investigate whether dual treatment with insulin‐like growth factor binding protein‐4 (IGFBP‐4), an agent that protects against early oxidative damage, can be effective in enhancing the therapeutic effect of VEGF following MI. Combined treatment with IGFBP‐4 enhanced VEGF‐induced angiogenesis and prevented cell damage via enhancing the expression of a key angiogenic factor angiopoietin‐1. Dual treatment with the two agents synergistically decreased cardiac fibrosis markers collagen‐I and collagen‐III following MI. Importantly, while the protective action of IGFBP‐4 occurs at an early stage of ischemic injury, the action of VEGF occurs at a later stage, at the onset angiogenesis. Our findings demonstrate that VEGF treatment alone is often not enough to protect against oxidative stress and promote post‐ischemic angiogenesis, whereas the combined treatment with IGFBP4 and VEGF can utilize the dual roles of these agents to effectively protect against ischemic and oxidative injury, and promote angiogenesis. These findings provide important insights into the roles of these agents in the clinical setting, and suggest new strategies in the treatment of ischemic heart disease.

Insulin-like growth factors (IGFs) are essential for oocyte maturation. Their bioavailability is regulated by their respective binding proteins (IGFBPs) and proteases. IGFBP-4 blocks the biological effects of IGFs. High IGFBP-4 expression has been associated with follicle atresia. We hypothesized that IGFBP-4 affects oocyte developmental competence during maturation. Therefore, the aim of this study was to examine the effect of IGFBP-4 on the developmental rate of bovine cumulus–oocyte complexes (COCs) during in vitro embryo production. Abattoir-derived COCs were matured with rbIGFBP-4 (2000, 540, and 54 ng/mL) compared to a control. Cumulus expansion, oocyte maturation, cleavage, blastocyst, and hatching rates were evaluated. Furthermore, blastocyst gene expression of SOCS2, STAT3, SLC2A1, SLCA3, BAX, and POU5F1 transcripts were quantified using RT-qPCR. No statistical differences were detected among the groups for cumulus expansion, maturation, cleavage, blastocyst rates, or all gene transcripts analyzed. However, at day 8 and 9, the number of total hatching and successfully hatched blastocysts was lower in 2000 ng/mL rbIGFBP-4 compared to the control (day 8: total hatching: 17.1 ± 0.21 vs. 31.2 ± 0.11%, p = 0.02 and hatched blastocyst 6.7 ± 0.31 vs. 21.5 ± 0.14%, p = 0.004; day 9 total hatching 36.4 ± 0.18 vs. 57.7 ± 0.10%, p = 0.009 and hatched blastocyst 18.2 ± 0.21 vs. 38.1 ± 0.11%, p = 0.004). We concluded that high concentrations of rbIGFBP-4 might negatively affect the subsequent ability of the embryo to hatch and possibly compromise further elongation.

Cardiovascular diseases (CVD) are among the leading causes of death and disability worldwide. Pregnancy-associated plasma protein-A (PAPP-A) is a matrix metalloprotease localized on the cell surface. One of the substrates that PAPP-A cleaves is the insulin-like growth factor binding protein-4 (IGFBP-4), a member of the family of proteins that bind insulin-like growth factor (IGF). Proteolysis of IGFBP-4 by PAPP-A occurs at a specific site resulting in formation of two proteolytic fragments – N-terminal IGFBP-4 (NT-IGFBP-4) and C-terminal IGFBP-4 (CT-IGFBP-4), and leads to the release of IGF activating various cellular processes including migration, proliferation, and cell growth. Increased levels of the proteolytic IGFBP-4 fragments correlate with the development of CVD complications and increased risk of death in patients with the coronary heart disease, acute coronary syndrome, and heart failure. However, there is no direct evidence that PAPP-A specifically cleaves IGFBP-4 in the cardiac tissue under normal and pathological conditions. In the present study, using a primary culture of rat neonatal cardiomyocytes as a model, we have demonstrated that: 1) proteolysis of IGFBP-4 by PAPP-A occurs in the conditioned medium of cardiomyocytes, 2) PAPP-A-specific IGFBP-4 proteolysis is increased when cardiomyocytes are transformed to a hypertrophic state. Thus, it can be assumed that the enhancement of IGFBP-4 cleavage by PAPP-A and hypertrophic changes in cardiomyocytes accompanying CVD are interrelated, and PAPP-A appears to be one of the activators of the IGF-dependent processes in normal and hypertrophic-state cardiomyocytes.

Background Bone is one of the major target tissues for Insulin-like Growth Factor I (IGF-I). Low doses of IGF-I were able to improve liver-associated osteopenia. In the present work, a model of partial IGF-I deficiency was used in order to provide insight into the mechanisms of the beneficial actions of IGF-I replacement therapy in bone. Methods Several proteins involved in osteoblastic/osteocyte and osteoclastic differentiation and activity were studied in the three experimental groups: control (CO) group (wild type mice, Igf +/+ , n = 10), heterozygous Igf +/- group with partial IGF-I deficiency (Hz, n = 10), and heterozygous Igf +/- mice treated with IGF-I for 10 days (Hz + IGF-I, n = 10). Results Data in this paper confirm that the simple partial IGF-I deficiency is responsible for osteopenia, determined by densitometry and histopathology. These findings are associated with a reduced gene expression of osteoprotegerin, sclerostin, calcitonin receptor (CTR), insulin-like growth factor binding protein 5 and RUNX2. IGF-I replacement therapy normalized CTR gene expression and reduced markers of osteoclastic activity. Conclusions Low doses of IGF-I constituted a real replacement therapy that normalized IGF-I serum levels improving the expression of most of these proteins closely involved in bone-forming, and reducing bone resorption by mechanisms related to osteoprotegerin, RANKL and PTH receptor.

Background Diabetic nephropathy (DN) is a type of progressive kidney disease affecting approximately 40% of patients with diabetes. Current DN diagnostic criteria predominantly rely on albuminuria and serum creatinine (sCr) levels. However, the specificity and reliability of both markers are limited. Hence, reliable biomarkers are required for early diagnosis to effectively manage DN progression. Methods In this study, a cohort of 159 individuals were clinically evaluated and the plasma levels of NGAL, IGFBP-1, IGFBP-3, and IGFBP-4 were determined using Multiplexing Assays. Additionally, the association between the plasma levels of NGAL, IGFBP-1, IGFBP-3, and IGFBP-4 in patients with DN were compared to those in patients with T2D without kidney disease and control participants. Results Circulating level of NGAL were significantly higher in people with DN compared to people with T2D and non-diabetic groups (92.76 ± 7.5, 57.22 ± 8.7, and 52.47 ± 2.9 mg/L, respectively; p  <  0.0001). IGFBP-4 showed a similar pattern, where it was highest in people with DN (795.61 ng/ml ±130.7) compared to T2D and non-diabetic people (374.56 ng/ml ±86.8, 273.06 ng/ml ±27.8 respectively, ANOVA p  <  0.01). The data from this study shows a significant positive correlation between NGAL and IGFBP-4 in people with DN ( ρ  = .620, p  <  0.005). IGFBP-4 also correlated positively with creatinine level and negatively with eGFR, in people with DN supporting its involvement in DN. Conclusion The data from this study shows a parallel increase in the plasma levels of NGAL and IGFBP-4 in DN. This highlights the potential to use these markers for early diagnosis of DN.

Insulin-like growth factor binding protein-4 (IGFBP-4) was reported to be associated with prognosis in several types of cancer; however, to the best of our knowledge, whether it is correlated with lung cancer has yet to be reported. In the present study, 102 pairs of lung cancer tissues and surrounding non-cancerous tissues (SNCTs) were collected. The IGFBP-4 levels in tissues were detected with immunohistochemistry. The relevance of IGFBP-4 to the survival of patients was assessed. The IGFBP-4 gene was knocked down, and its function in the proliferation of lung cancer cells was measured. The percentage of lung cancer tissues with higher IGFBP-4 expression than SNCTs (51.9%) was increased compared with the percentage with similar (11.76%) or lower (36.27%) IGFBP-4 expression. Patients with higher IGFBP-1 expression exhibited a shorter median survival time. IGFBP-1 was associated with metastasis, lung cancer stages and malignancy, but not with age, sex or tumor size. Lung cancer cells with stably knocked down IGFBP-4 showed an inhibitory proliferation rate. The present study identified that IGFBP-4 was adversely associated with the prognosis of lung cancer patients. IGFBP-4 knockdown prohibited lung cancer cell growth. The present study provides a potential marker for lung cancer diagnosis and a possible target for lung cancer therapy.

Insulin-like growth factor binding protein-4 (IGFBP-4) fragments have been shown to be associated with cardiometabolic diseases. Anthocyanins as a subgroup of natural polyphenols could have benefits on treating cardiometabolic diseases. The aim of this study was to examine the effects of purified anthocyanins on serum IGFBP-4 fragments and glycemic control in patients with fasting hyperglycemia. A set of 121 participants with elevated fasting glucose (≥5.6 mmol/L), who were originally randomly assigned to anthocyanins (320 mg/day) or placebo groups, were included in this study. Serum IGFBP-4 fragments, fasting and postload glucose, insulin, and C-peptide after a three-hour oral glucose tolerance test (OGTT) were measured at baseline and at the end of 12 weeks. Compared with placebo, anthocyanins increased serum IGFBP-4 fragments (net change 8.33 ng/mL, 95% CI [1.2, 15.47], =0.023) and decreased fasting glucose (-0.4 mmol/L [-0.71, -0.1], =0.01), 2-hour C-peptide (-1.02 ng/mL [-1.99, -0.04], =0.041) and the 3-hour area under the curve (AUC) of C-peptide (-2.19 [-4.11, -0.27], =0.026). No other significant difference in parameters for glycemic control and insulin resistance was observed. Anthocyanins supplementation for 12 weeks improved serum IGFBP-4 fragments and decreased fasting glucose and postload C-peptide in patients with fasting hyperglycemia. Further studies are needed to confirm our findings and clarify the potential mechanism. ClinicalTrials.gov, NCT02689765. Registered on 6 February 2016, https://clinicaltrials.gov/ct2/show/NCT02689765.