Cardiotrophin-1 Research Articles

The role of Cardiotrophin-1 and echocardiography in early detection of subclinical diabetic cardiomyopathy in children and adolescents with type 1 diabetes mellitus.

To assess the role of Cardiotrophin-1 (CT-1) and echocardiography in early detection of subclinical Diabetic Cardiomyopathy (DCM) in children with type 1 Diabetes Mellitus (T1D). This case-control study included two groups of children and adolescents aged between 7 and 18. Group (1) included forty patients with T1D (duration > 5 years) regularly followed at the children's hospital of Cairo University, and Group (2) included forty age and sex-matched healthy subjects as a control group. The serum level of CT-1 was measured, and conventional echocardiography, tissue Doppler imaging (TDI), and 2D speckle tracking echocardiography were performed. The level of CT-1 in the cases ranged from 11 to 1039.4 pg/ml with a median (IQR) of 19.4 (16.60-25.7) pg/ml, while its level in the control group ranged from 10.8 to 162.6 pg/ml with a median (IQR) of 20.2 (16.2-24.8) pg/ml. CT-1 levels showed no statistically significant difference between cases and controls. Patients had significantly higher mean left ventricle E/E' ratio (p<0.001), lower mean 2D global longitudinal strain (GLS) of the left ventricle (LV) (p<0.001), and lower mean GLS of the right ventricle (RV) (p<0.001) compared to controls. Ofpatients with diabetes, 75 % had LV diastolic dysfunction, 85 % had RV diastolic dysfunction, 97.5 % had LV systolic dysfunction, and 100 % had RV systolic dysfunction. Non-conventional echocardiography is important for early perception of subclinical DCM in patients with T1D. CT-1 was not specific for early detection of DCM.

Cardiotrophin-1 therapy reduces disease severity in a murine model of glomerular disease.

Cardiotrophin-1 (CT-1), a member of the interleukin (IL)-6 cytokine family, has renoprotective effects in mouse models of acute kidney disease and tubulointerstitial fibrosis, but its role in glomerular disease is unknown. To address this, we used the mouse model of nephrotoxic nephritis to test the hypothesis that CT-1 also has a protective role in immune-mediated glomerular disease. Using immunohistochemistry and analysis of single-cell RNA-sequencing data of isolated glomeruli, we demonstrate that CT-1 is expressed in the glomerulus in male mice, predominantly in parietal epithelial cells and is downregulated in mice with nephrotoxic nephritis. Furthermore, analysis of data from patients revealed that human glomerular disease is also associated with reduced glomerular CT-1 transcript levels. In male mice with nephrotoxic nephritis and established proteinuria, administration of CT-1 resulted in reduced albuminuria, prevented podocyte loss, and sustained plasma creatinine, compared with mice administered saline. CT-1 treatment also reduced fibrosis in the kidney cortex, peri-glomerular macrophage accumulation and the kidney levels of the pro-inflammatory mediator complement component 5a. In conclusion, CT-1 intervention therapy delays the progression of glomerular disease in mice by preserving kidney function and inhibiting renal inflammation and fibrosis.

Association between Human Blood Proteome and the Risk of Myocardial Infarction.

The objective of this study is to estimate the causal relationship between plasma proteins and myocardial infarction (MI) through Mendelian randomization (MR), predict potential target-mediated side effects associated with protein interventions, and ensure a comprehensive assessment of clinical safety. From 3 proteome genome-wide association studies (GWASs) involving 9775 European participants, 331 unique blood proteins were screened and chosed. The summary data related to MI were derived from a GWAS meta-analysis, incorporating approximately 61,000 cases and 577,000 controls. The assessment of associations between blood proteins and MI was conducted through MR analyses. A phenome-wide MR (Phe-MR) analysis was subsequently employed to determine the potential on-target side effects of protein interventions. Causal mediators for MI were identified, encompassing cardiotrophin-1 (CT-1) (odds ratio [OR] per SD increase: 1.16; 95% confidence interval [CI]: 1.13-1.18; p = 1.29 ), Selenoprotein S (SELENOS) (OR: 1.16; 95% CI: 1.13-1.20; p = 4.73 ), killer cell immunoglobulin-like receptor 2DS2 (KIR2DS2) (OR: 0.93; 95% CI: 0.90-0.96; p = 1.08 ), vacuolar protein sorting-associated protein 29 (VPS29) (OR: 0.92; 95% CI: 0.90-0.94; p = 8.05 ), and histo-blood group ABO system transferase (NAGAT) (OR: 1.05; 95% CI: 1.03-1.07; p = 1.41 ). In the Phe-MR analysis, memory loss risk was mediated by CT-1, VPS29 exhibited favorable effects on the risk of 5 diseases, and KIR2DS2 showed no predicted detrimental side effects. Elevated genetic predictions of KIR2DS2 and VPS29 appear to be linked to a reduced risk of MI, whereas an increased risk is associated with CT-1, SELENOS, and NAGAT. The characterization of side effect profiles aids in the prioritization of drug targets. Notably, KIR2DS2 emerges as a potentially promising target for preventing and treating MI, devoid of predicted detrimental side effects.

Calcium Dibutyryl Adenosine Cyclophosphate Enhances the Effect of Metoprolol in Treating Older Adults With Heart Failure Combined With Arrhythmia

To explore the effect and safety of calcium dibutyryl adenosine cyclophosphate (dbcAMP-Ca) combined with metoprolol in the treatment of older adults with heart failure combined with arrhythmia. A total of 102 elderly patients with heart failure combined with arrhythmia were enrolled in our hospital between February 2021 and April 2023. The list of patients enrolled was entered into a random database by independent staffs not involved in the study and random assignment sequences were generated by the SAS9.4 software. Then, the 102 elderly patients were divided into a control group ( n=51) and an experimental group ( n=51). Patients in the control group were given metoprolol at an initial dose of 6.25 mg/d, which was gradually increased to the target dose of 25 mg/d. Patients in the experimental group were given 40 mg of dbcAMP-Ca once a day via intravenous drip in addition to the treatment given to the control group. Both groups were treated for 4 weeks. The rate of effective response to clinical treatment (the number of cases achieving significant effects and those achieving some effects divided by the total number of cases in the group) was defined as the main outcome index. Secondary indexes included cardiac function, heart rate variability, exercise ability, hemorheology, myocardial injury indexes, inflammatory indexes, and the occurrence of adverse reactions. The rate of effective response to clinical treatment was higher in the experimental group than that in the control group (94.12% [48/51] vs. 78.43% [40/51], P<0.05). After treatment, the left ventricular end-diastolic and end-systolic dimensions (LVEDD and LVESD) and the interventricular septal thickness (IVS) were lower in the experimental group than those in the control group, while the left ventricular ejection fraction (LVEF) and the stroke volume (SV) were higher in the experimental group than those in the control group ( P<0.05). In terms of heart rate variability after treatment, the standard deviation of all the normal-to-normal intervals/the average of all the normal-to-normal intervals (SDNN/SDANN), the percentage of NN50 in the total number of normal-to-normal intervals (PNN50%), and the root mean square of the differences between adjacent normal-to-normal intervals/root mean square differences of successive R-R intervals (RMSSD) were higher in the experimental group than those in the control group ( P<0.05). In terms of exercise capacity after treatment, the subjects in the experimental group covered more distance in the 6-min walk test than those in the control group did ( P<0.05). In terms of the hemorheology indexes after treatment, the levels of platelet aggregation rate (PAgT), fibrinogen (FIB), erythrocyte sedimentation rate (ESR), and whole blood viscosity (ηb) were lower in the experimental group than those in the control group ( P<0.05). In terms of the myocardial injury indexes after treatment, the levels of serum N-terminal pro-brain natriuretic peptide (NT-pro BNP) and cardiac troponin I (cTnI) were lower in the experimental group than those in the control group, while the levels of insulin-like growth factor 1 (IGF-1) and cardiotrophin 1 (CT-1) were higher in the experimental group than those in the control group ( P<0.05). In terms of the inflammatory indexes after treatment, the levels of interleukin-6 (IL-6), high-sensitive C-reactive protein (hs-CRP), and tumor necrosis factor-α (TNF-α) were lower in the experimental group than those in the control group ( P<0.05). The incidence of adverse reactions in the experimental group (9.80%) and that in the control group (7.84%) were comparable ( P>0.05). The use of dbcAMP-Ca in addition to metoprolol can effectively improve cardiac function, heart rate variability, and exercise tolerance, while inhibiting inflammatory response in elderly patients with heart failure combined with arrhythmia, with high medication safety. The combination medication shows better safety and therapeutic effects than those of metoprolol used alone.

Interleukin-6 Family of Cytokines in Cancers.

Nine soluble ligands [interleukin-6 (IL-6), interleukin-11 (IL-11), leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine, interleukin-27 (IL-27), and interleukin-31] share the ubiquitously expressed transmembrane protein-glycoprotein-130 beta-subunit (gp130) and thus form IL-6 family cytokines. Proteins that may be important for cancerogenesis, CT-1, IL-11, IL-27, LIF, OSM, and CNTF, belong to the superfamily of IL-6. Cytokines such as IL-6, IL-11, and IL-27 are better investigated in comparison with other members of the same family of cytokines, eg, CT-1. Gp130 is one of the main receptors through which these cytokines exert their effects. The clinical implication of understanding the pathways of these cytokines in oncology is that targeted therapy to inhibit or potentiate cytokine activity may lead to remission in some cases.

Evaluation of selected circulating cytokines from the IL-6 family - interleukin 6, oncostatin M, and cardiotrophin-1 - in gastro-entero-pancreatic and bronchial neuroendocrine tumours.

The incidence of neuroendocrine tumours (NETs) increased over the last years. Most of them are non-functioning, and the course of the disease is asymptomatic for a long time. This results in late diagnosis at an advanced stage. The aim of our study was the evaluation of selected circulating cytokines of interleukin-6 family - interleukin 6 (IL-6), oncostatin M (OSM), and cardiotrophin-1 (CT1) - in NETs. The study group comprised 80 patients (56%) in several subgroups, including gastroenteropancreatic (GEPNETs, n = 64, 80%) and bronchopulmonary neuroendocrine tumours (BPNETs, n = 16; 20%). Serum IL-6, OSM, and CT1 concentrations were tested using ELISA. The median concentration of IL-6 was 41.5 pg/ml in the study group and 32.6 pg/ml in the control group, and the difference was statistically significant (p < 0.001). The concentration of OSM was significantly lower in the study group than in the control group (p < 0.001), at 105.6 pg/ml and 115.5 pg/ml, respectively. There was a significant difference (p < 0.01) in concentration of CT1 in the study group (222.0 pg/ml) and controls (267.2 pg/ml). Our investigation into selected IL-6 family cytokines revealed differential modulation of signal transduction pathways. These findings suggest that despite utilising a common signalling transducer, individual IL-6 family cytokines exert distinct biological effects on neuroendocrine tumour development. Notably, IL-6 appears to promote tumourigenesis, while OSM and CT1 exhibit inhibitory effects on gastro-entero-pancreatic and bronchial neuroendocrine tumour development. Further studies are necessary to validate the diagnostic utility of IL-6 family cytokines in NETs.

Investigation of Serum Cardiotrophin-1 Concentrations in Pregnant Women with Gestational Diabetes Mellitus.

We aimed to investigate cardiotrophin-1 (CT-1) concentrations in the serum of pregnant women with gestational diabetes mellitus (GDM). This prospective non-interventional cohort study was conducted with 160 pregnant women who applied to the Umraniye Training and Research Hospital, Department of Obstetrics and Gynecology between October 2022 and May 2023. The GDM group was formed from 80 pregnant women who were diagnosed with GDM according to the 75-g OGTT. The control group consisted of 80 healthy pregnant women who were matched with the GDM group in terms of age and body mass index and had a normal 75-g OGTT result. Two groups were compared in terms of maternal serum CT-1 concentrations. Both groups were similar in terms of demographic features and the gestational week at blood sampling for CT-1 (p>0.05 for each). The mean maternal serum CT-1 concentration was found to be 1420.9 pg/ml in the GDM group, while it was determined as 1455 pg/ml in the control group (p=0.738). When the GDM and control groups were divided into two subgroups, normal weight and overweight according to the participants' BMI, serum CT-1 concentrations were found to be similar in these four groups (p=0.084). When the GDM group was divided into two groups of diet-only and the insulin-using group for blood glucose regulation and compared with the control group, the three groups were also similar in terms of serum CT-1 concentrations (p=0.189). CT-1 is an adipokine involved in the regulation of glucose metabolism and has been suggested to be associated with the pathophysiology of diabetes mellitus. In this study, serum CT-1 concentrations were found to be similar in the group with GDM and the group with normal glucose tolerance. Whether CT-1 contributes to the development of GDM is currently unclear and requires further investigation.

Investigation of maternal serum cardiotrophin-1 concentrations in pregnant women with preeclampsia; a prospective case-control study

Objective We aimed to investigate the cardiotrophin-1 (CT-1) concentrations in the serum of pregnant women with preeclampsia Methods This cross-sectional study was conducted with 88 pregnant women who applied to the Umraniye Training and Research Hospital Gynecology and Obstetrics Clinic between May 2022 and September 2022. The preeclampsia group consisted of 44 pregnant women diagnosed with preeclampsia, and the control group consisted of 44 healthy pregnant women matched with the preeclampsia group in terms of age and body mass index. Demographic characteristics, ultrasound and laboratory findings, perinatal outcomes, and maternal serum CT-1 concentrations were recorded. Results Both groups were similar in terms of demographic features and the gestational week at blood sampling for CT-1. Preeclampsia and control groups were compared in terms of maternal serum CT-1 concentrations and no significant difference was found between the two groups (2061.4 pg/ml, 2168.5 pg/ml, respectively, p = .516). The preeclampsia group was divided into subgroups as mild and severe preeclampsia according to the severity of the disease and early-onset and late-onset preeclampsia according to the time of onset and compared with the control group in terms of maternal serum CT-1 concentration, no significant difference was found between the groups (p > .005, for all). Conclusion The serum CT-1 concentration of women whose pregnancy was complicated with preeclampsia was found to be similar to that of healthy controls. Although it has been shown in the literature that high serum CT-1 concentrations are associated with hypertensive heart diseases, its role in the pathophysiology of preeclampsia remains unclear.

Maresin 1 Exerts a Tissue-Specific Regulation of Adipo-Hepato-Myokines in Diet-Induced Obese Mice and Modulates Adipokine Expression in Cultured Human Adipocytes in Basal and Inflammatory Conditions.

This study analyses the effects of Maresin 1 (MaR1), a docosahexaenoic acid (DHA)-derived specialized proresolving lipid mediator with anti-inflammatory and insulin-sensitizing actions, on the expression of adipokines, including adiponectin, leptin, dipeptidyl peptidase 4 (DPP-4), cardiotrophin-1 (CT-1), and irisin (FNDC5), both in vitro and in in vivo models of obesity. The in vivo effects of MaR1 (50 μg/kg, 10 days, oral gavage) were evaluated in epididymal adipose tissue (eWAT), liver and muscle of diet-induced obese (DIO) mice. Moreover, two models of human differentiated primary adipocytes were incubated with MaR1 (1 and 10 nM, 24 h) or with a combination of tumor necrosis factor-α (TNF-α, 100 ng/mL) and MaR1 (1-200 nM, 24 h) and the expression and secretion of adipokines were measured in both models. MaR1-treated DIO mice exhibited an increased expression of adiponectin and Ct-1 in eWAT, increased expression of Fndc5 and Ct-1 in muscle and a decreased expression of hepatic Dpp-4. In human differentiated adipocytes, MaR1 increased the expression of ADIPONECTIN, LEPTIN, DPP4, CT-1 and FNDC5. Moreover, MaR1 counteracted the downregulation of ADIPONECTIN and the upregulation of DPP-4 and LEPTIN observed in adipocytes treated with TNF-α. Differential effects for TNF-α and MaR1 on the expression of CT-1 and FNDC5 were observed between both models of human adipocytes. In conclusion, MaR1 reverses the expression of specific adipomyokines and hepatokines altered in obese mice in a tissue-dependent manner. Moreover, MaR1 regulates the basal expression of adipokines in human adipocytes and counteracts the alterations of adipokines expression induced by TNF-α in vitro. These actions could contribute to the metabolic benefits of this lipid mediator.

Combination of decaffeinated green coffee and decaffeinated green tea ameliorates cardiomyopathy through cardiotrophin-1-dependent expression regulation in a metabolic syndrome rat model: a proposed mechanism

BackgroundCardiovascular diseases (CVD) are the primary medical manifestation of metabolic syndrome (MetS). Hypoxia is also involved in the pathogenesis of CVD. Since dietary intervention significantly improved the physiological condition in MetS, the development of functional food to complement conventional medical therapy is essential. Among several standard consumable products, decaffeinated green tea (DGT) and decaffeinated green coffee (DGC) have excellent activity in managing MetS-induced CVD. However, the mechanism underlying their protective activity is poorly understood. This study aimed to understand the cardio-protective activity of DGT, DGC, and a combination of the two (DGT + DGC) in managing MetS-induced CVD in vivo and in silico.ResultsThe MetS condition led to the upregulation of Cardiotrophin-1 (CT-1), Signal Transducer and Activator of Transcription 3 (STAT3), GATA binding protein 4 (GATA4), and B-type Natriuretic Peptide (BNP) beyond the levels of the normal (N) group, while administration of DGT, DGC, and DGT + DGC significantly decreased the expression of those genes compared with the levels of the N group (p < 0.05). The computational analysis showed that the protective role of DGT, DGC, and DGT + DGC might be achieved through AKT1 inhibition by several bioactive components present in DGT and DGC. The analysis also defined the improvement in cardio-protective activity by combining DGT and DGC.ConclusionsThe administration of DGT, DGC, or DGT + DGC repaired cardiac dysfunction parameters through indirect regulation of the CT-1 signaling axis by inhibiting AKT1 activity.

Serum Cardiotrophin-1 Concentration Is Negatively Associated with Controlled Attenuation Parameters in Subjects with Non-Alcoholic Fatty Liver Disease

Since non-alcoholic fatty liver disease (NAFLD) is highly associated with obesity, cardiovascular disease, and diabetes, biomarkers for the diagnosis of NAFLD have become an important issue. Although cardiotrophin-1 (CT-1) has a protective effect on the liver in NAFLD animal models, the serum levels of CT-1 in human subjects with NAFLD were still unknown. The present study aimed to investigate the relationship between the circulating concentration of CT-1 and the severity of hepatic steatosis graded by the value of the controlled attenuation parameter (CAP) in humans. The study was designed as a cross-sectional study, and a total of 182 subjects were enrolled. Hepatic steatosis measurement was carried out with a Firoscan® device and recorded by CAP. The enrolled study subjects were categorized into CAP < 238 dB/m, 238 ≤ CAP ≤ 259 dB/m, 260 ≤ CAP ≤ 290 dB/m, and CAP > 290 dB/m. Serum CT-1 concentrations were determined by enzyme-linked immunosorbent assay. The association between the serum CT-1 concentration and NAFLD was examined by multivariate linear regression analysis. Body mass index, percentage of body fat, systolic and diastolic blood pressure, alanine aminotransferase (ALT), cholesterol, triglyceride, hemoglobin A1c and homeostatic model assessment for insulin resistance (HOMA-IR) were significantly increased in groups with higher CAP value, whereas high-density lipoprotein cholesterol was significantly decreased. In addition, serum CT-1 concentrations were significantly decreased in subjects with higher CAP values. In multivariate linear regression models, including age, sex, body fat percentage, CAP, high sensitivity- C reactive protein, uric acid, creatinine, ALT, total cholesterol, and HOMA-IR, only age, CAP and uric acid independently associated with CT-1 levels. Moreover, having NAFLD was independently associated with CT-1 after adjustment for sex, obesity and type 2 diabetes. Serum CT-1 concentrations are decreased in subjects with NAFLD and negatively associated with CAP.

Osteoprotegerin, Chitinase 3-like Protein 1, and Cardiotrophin-1 as Potential Biomarkers of Obstructive Sleep Apnea in Adults-A Case-Control Study.

Obstructive sleep apnea (OSA) is a prevalent, underdiagnosed disease and is considered a risk factor for cardiovascular diseases, depression, accidents, and stroke. Recent clinical practice guidelines for OSA expressed the need for a new clinical tool that establishes the Apnea-Hypopnea Index (AHI) to determine the disease burden. The serum and plasma concentrations of Osteoprotegerin (OPG), Chitinase 3-like protein 1 (YKL-40), and Cardiotrophin-1 (CT-1) in 80 subjects-52 OSA patients, 27 moderate (15 ≤ AHI ˂ 30) and 25 severe (AHI ≥ 30), and 28 non-OSA controls (AHI 0-5)-were determined. Moreover, the Total Oxidative Status (TOS), Total Antioxidative Status (TAS), and Oxidative Stress Index (OSI) were assessed in the serum and plasma to evaluate whether the severity of OSA and the concentrations of OPG, YKL-40, and CT-1 correlate with the oxidative/reductive status. The serum and plasma concentrations of YKL-40 and CT-1 were higher in the OSA group, whereas the serum and plasma concentrations of OPG were lower compared to the control group. The concentrations of OPG, YKL-40, and CT-1 in the serum and plasma correlated with AHI; however, a better correlation of the concentrations was obtained for the above-mentioned proteins in the plasma. The concentrations of YKL-40 and CT-1 in the serum and OPG in the plasma show better diagnostic capabilities for moderate and severe OSA than the concentrations of YKL-40 and CT-1 in the plasma and the concentrations of OPG in the serum.

Uncovering the promiscuous activity of IL-6 proteins: A multi-dimensional analysis of phylogeny, classification and residue conservation.

The IL‐6 family of cytokines, known for their pleiotropic behavior, share binding to the gp130 receptor for signal transduction with the necessity to bind other receptors. Leukemia inhibitory factor receptor is triggered by the IL‐6 family proteins: leukemia inhibitory factor (LIF), oncostatin‐M (OSM), cardiotrophin‐1 (CT‐1), ciliary neurotrophic factor (CNTF), and cardiotrophin‐like cytokine factor 1 (CLCF1). Besides the conserved binding sites to the receptor, not much is known in terms of the diversity and characteristics of these proteins in different organisms. Herein, we describe the sequence analysis of LIF, OSM, and CT‐1 from several organisms, and m17, a LIF ortholog found in fishes, regarding its phylogenetics, intrinsic properties, and the impact of conserved residues on structural features. Sequences were identified in seven classes of vertebrates, showing high conservation values in binding site III, but protein‐dependent results on binding site II. GRAVY, isoelectric point, and molecular weight parameters were relevant to differentiate classes in each protein and to enable, for the first time and with high fidelity, the prediction of both organism class and protein type just using machine learning approaches. OSM sequences from primates showed an increased BC loop when compared to the remaining mammals, which could influence binding to OSM receptor and tune signaling pathways. Overall, this study highlights the potential of sequence diversity analysis to understand IL‐6 cytokine family evolution, showing the conservation of function‐related motifs and evolution of class and protein‐dependent characteristics. Our results could impact future medical treatment of disorders associated with imbalances in these cytokines.

Empagliflozin rescues primary murine cardiac fibroblasts, but not cardiomyocytes, from hypoxia-reoxygenation injury through STAT3-mediated cascades

Abstract Introduction Empagliflozin (EMPA) is a selective sodium glucose co-transporter 2 inhibitor (SGLT2i) and an established drug against type 2 diabetes mellitus. Cardiovascular clinical outcome trials on EMPA have shown a reduced mortality rate related to major cardiovascular events, but the precise mechanism of action remains elusive. We have previously proved that chronic EMPA administration reduces infarct size in an in vivo murine model of ischemia / reperfusion injury, irrespective of the diabetic status. The cardioprotective effect of EMPA was attributed to the increase of Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation. Purpose In this study we aimed to decipher the cell specific effects of EMPA on primary adult ventricular murine cardiomyocytes (pAVMCs) and primary murine cardiac fibroblasts (pMCFs), subjected to hypoxia/reoxygenation (HYP/REO) and to 1) investigate the effect of EMPA on cell death, and 2) reveal the mechanism of cardioprotection. Methods PAVMCs and pMCFs were isolated from adult C57BL/6 murine hearts (n=4–6) and were incubated with EMPA (500nM–100nM) for 24 hours. Cells were then subjected to 3 hours of HYP (99% N2), followed by 1 hour of REO. STATTIC, a selective STAT3 inhibitor was used (500nM–1μM) to determine the contribution of STAT3 on the observed effect. MTT assay was performed at the end of REO to determine cell viability. To unravel the mechanism of cardioprotection, the experimental protocol was repeated, and the cells were either stained with dihydroethidium (DHE) dye to determine relative oxidative stress changes or were harvested for isolation of total protein content. We focused on STAT3 and Akt kinase as key mediators of the cardioprotective survivor activating factor enhancement (SAFE) and the reperfusion injury salvage kinase (RISK) pathways. We also investigated the expression of Cardiotrophin-1 (CT-1), as a potential upstream mediator of STAT3 phosphorylation. Results The evaluation of cell death revealed that pMCFs viability was significantly increased upon EMPA treatment. Added to this, STATTIC co-treatment with EMPA blunted the protective effect on pMCFs, which indicates that EMPA's protection is STAT3-mediated. Oxidative stress remained unaltered by the treatments. Investigation of the molecular pathways that are responsible for the increased viability of pMCFs revealed that EMPA treatment induces an increased phosphorylation of STAT3 and an increase in CT-1 expression, which are both reversed by STATTIC. Akt phosphorylation and expression remained unchanged by EMPA treatment. Notably, the effect of EMPA on pAVMCs' viability was negligible. Conclusion(s) EMPA does not protect pAVMCs, from HYP/REO injury. EMPA rescues the pMCFs in a STAT-3 dependent manner which indicates that EMPA's cardioprotective effect is cell specific and implicates the SAFE pathway. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Boehringer Ingelheim International GmbHGrant title: “Investigation of the distinct effects of Empagliflozin on different cell populations of the healthy myocardium”

Кардіотрофін-1 як можливий маркер ремоделювання міокарда у хворих з есенціальною гіпертензією при носійстві поліморфних варіантів кодувального гена

Мета роботи – поліпшити діагностику ремоделювання лівого шлуночка у хворих з есенціальною гіпертензією (ЕГ) шляхом визначення концентрації кардіотрофіну-1 (КТ-1) у плазмі крові в носіїв поліморфних варіантів гена кардіотрофіну-1 (rs8046707).Матеріали і методи. У дослідження залучено 100 чоловіків віком 40–60 років, мешканців Поділля з ЕГ різної тяжкості. До першої групи увійшли пацієнти з ЕГ II стадії, середній вік – (50,62±0,73) року, до другої групи – пацієнти з ЕГ, ускладненою хронічною серцевою недостатністю (ХСН), середній вік – (51,86±0,81) року. Структурно-функціональні показники міокарда оцінювали за допомогою ультразвукового дослідження серця. Поліморфізм гена КТ-1 (rs8046707) визначали за допомогою методу полімеразної ланцюгової реакції. Концентрацію КТ-1 оцінювали з використанням методу імуноферментного аналізу. Результати та обговорення. Серед чоловіків з ЕГ різної тяжкості статистично значуще частіше реєструються носії генотипів GA+АА – 65,00 % (n=65), ніж генотипу GG – 35,00 % (n=35) (р&lt;0,05). Встановлено, що в носіїв будь-якого поліморфного варіанта гена КТ-1, чоловіків з гіпертрофією лівого шлуночка (ГЛШ) та ХСН на тлі ЕГ найчастіше трапляється концентрична ГЛШ. Водночас рівень КТ-1 у плазмі крові у хворих на ЕГ не тільки є вищим при більшій масі міокарда лівого шлуночка, а й асоційований з носійством певного варіанта кодувального гена. Зокрема, при ЕГ рівні концентрації КТ-1 у плазмі крові при ексцентричній ГЛШ статистично значуще більші в носіїв генотипів GA+АА гена КТ-1 (р&lt;0,05). При ЕГ з ХСН, незалежно від поліморфізму гена КТ-1, концентрація цього пептиду в плазмі крові при різних варіантах ГЛШ вища, ніж у хворих на ЕГ II стадії (р&lt;0,05).Висновки. Таким чином, у чоловіків з ЕГ ІІ стадії та ЕГ з ХСН, носіїв поліморфних варіантів гена КТ-1, статистично значуще частіше траплялася концентрична ГЛШ. Чоловіки з ЕГ ІІ стадії, носії генотипів GA+АА, мають статистично значуще вищий рівень КТ-1 у плазмі крові при концентричній ГЛШ (р&lt;0,05). У разі розвитку ХСН на тлі ЕГ рівень КТ-1 у плазмі крові при носійстві будь-якого варіанта кодувального гена вищий, ніж при ЕГ ІІ стадії.

Induction of Stem-Cell-Derived Cardiomyogenesis by Fibroblast Growth Factor 10 (FGF10) and Its Interplay with Cardiotrophin-1 (CT-1)

Simple SummaryCardiovascular diseases are worldwide one of the leading contributors of mortality, and among multiple therapeutic approaches, stem cell therapy has been introduced as a robust therapeutic strategy to alleviate related symptoms and restore cardiac functions. Prior to this, however, for successful cell therapy, an adequate number of functional and safe cardiac cells needs to be generated. For this purpose, our approach was boosting the proliferative capacity of stem cell-derived cardiomyocytes using growth factors, such as fibroblast growth factor 10 (FGF10) and cardiotrophin-1 (CT-1). Our results demonstrated that FGF10 and CT-1 substantially increased the number of cardiac cells that originated from stem cells. In molecular assays, to assess RNA and protein level alterations, the enhanced presence of specific markers for cardiac cells after treatment of stem cells with FGF10 and/or CT-1 was confirmed. This inducing potential of cardiac cells can particularly be applicable in the cell replacement-based therapies of cardiac infarction. This research sheds light on the putative effect of FGF10 and CT-1 in the transition of stem cells to cardiac cells, leading to the repair and survival of the heart.For heart regeneration purposes, embryonic stem cell (ES)-based strategies have been developed to induce the proliferation of cardiac progenitor cells towards cardiomyocytes. Fibroblast growth factor 10 (FGF10) contributes to cardiac development and induces cardiomyocyte differentiation in vitro. Yet, among pro-cardiogenic factors, including cardiotrophin-1 (CT-1), the hyperplastic function of FGF10 in cardiomyocyte turnover remains to be further characterized. We investigated the proliferative effects of FGF10 on ES-derived cardiac progenitor cells in the intermediate developmental stage and examined the putative interplay between FGF10 and CT-1 in cardiomyocyte proliferation. Mouse ES cells were treated with FGF10 and/or CT-1. Differential expression of cardiomyocyte-specific gene markers was analyzed at transcript and protein levels. Substantial upregulation of sarcomeric α-actinin was detected by qPCR, flow cytometry, Western blot and immunocytochemistry. FGF10 enhanced the expression of other structural proteins (MLC-2a, MLC-2v and TNNT2), transcriptional factors (NKX2-5 and GATA4), and proliferation markers (Aurora B and YAP-1). FGF10/CT-1 co-administration led to an upregulation of proliferation markers, suggesting the synergistic potential of FGF10 + CT-1 on cardiomyogenesis. In summary, we provided evidence that FGF10 and CT-1 induce cardiomyocyte structural proteins, associated transcription factors, and cardiac cell proliferation, which could be applicable in therapies to replenish damaged cardiomyocytes.

DO ANDROGENS PREDICT CARDIOVASCULAR RISK INCLUDING CARDIOTROPHIN-1 LEVELS in PATIENTS WITH OBESE and LEAN POLYCYSTIC OVARY SYNDROME.

We aimed to investigate Cardiotrophin-1 (CT-1) levels along with other markers of cardiovascular disease and the association of androgen levels with these parameters in both lean and overweight or obese PCOS patients. The study included 90 overweight or obese PCOS patients with metabolic syndrome (MS) and 80 lean PCOS patients without MS. The control group consisted of 140 healthy females. Anthropometric measurements, plasma glucose, insulin, lipid and hormone profile, homocysteine, hs-CRP, CT-1 levels and carotid-IMT were evaluated in all study subjects. Fasting insulin, HOMA values were significantly higher in obese PCOS patients. Total testosteron levels were higher in both PCOS groups with respect to both controls. Serum homocysteine, hs-CRP, CT-1 and carotid-IMT values were significantly higher in both PCOS groups compared to controls (p=0.001, pCIMT: 0.005). CT-1 was positively correlated with insulin, HOMA, total testosterone, homocysteine, hs-CRP and carotid IMT. After multiple regression analysis, CT-1 was significantly positively correlated with total testosterone, hs-CRP and carotid IMT. CT-1 was associated with other cardiovascular risk markers and its use as a cardiovascular risk marker might be suggested. Cardiovascular risk was increased even in lean PCOS patients without MS and it might be associated with elevated androgen levels.

Diagnostic and Prognostic Role of Cardiotrophin-1 in Patients with Heart Failure

The review is devoted to the diagnostic and prognostic role of cardiotrophin-1 (CT-1) in patients with acute and chronic heart failure (CHF). The article provides information on the main regulatory effect of CT-1 in relation to the processes of cardiovascular remodeling. We considered the prospects of monitoring the plasma concentration of CT-1for the individualization of the assessment of cardiovascular risk in patients with CHF at various stages of the cardiovascular continuum. MeSH words: heart failure, cardiotrophin-1, hypertrophy, fibrosis, cytokines.

Influences of the IL-6 cytokine family on bone structure and function

The IL-6 family of cytokines comprises a large group of cytokines that all act via the formation of a signaling complex that includes the glycoprotein 130 (gp130) receptor. Despite this, many of these cytokines have unique roles that regulate the activity of bone forming osteoblasts, bone resorbing osteoclasts, bone-resident osteocytes, and cartilage cells (chondrocytes). These include specific functions in craniofacial development, longitudinal bone growth, and the maintenance of trabecular and cortical bone structure, and have been implicated in musculoskeletal pathologies such as craniosynostosis, osteoporosis, rheumatoid arthritis, osteoarthritis, and heterotopic ossifications. This review will work systematically through each member of this family and provide an overview and an update on the expression patterns and functions of each of these cytokines in the skeleton, as well as their negative feedback pathways, particularly suppressor of cytokine signaling 3 (SOCS3). The specific cytokines described are interleukin 6 (IL-6), interleukin 11 (IL-11), oncostatin M (OSM), leukemia inhibitory factor (LIF), cardiotrophin 1 (CT-1), ciliary neurotrophic factor (CNTF), cardiotrophin-like cytokine factor 1 (CLCF1), neuropoietin, humanin and interleukin 27 (IL-27).

Increased Expression of Cardiotrophin-1 in Cardiomyopathy Patients.

Cardiomyopathy (CM) is a condition of cardiac dysfunction. It is one of the leading causes of mortality in which both genetic and environmental factors are involved. Cardiotrophin-1 (CT-1) level in plasma is associated with CM. It affects the cardiomyocyte differentiation. To evaluate the expression of CT-1 in cardiomyopathy, this study was done on CM subjects attending the Fatima Memorial Hospital, Lahore, Pakistan, between January and June, 2016. A total of 40 subjects were enrolled who were divided into two groups; CM group (n = 20) and a control group (n = 20). A self-designed questionnaire was filled in by each subject to collect data regarding age, body mass index (BMI) and CM history. RNA was isolated from blood after its quantification, cDNA was prepared and reverse-transcriptase-polymerase chain reaction (RT-PCR) was performed for expression of CT-1. The mean age in CM subjects was 40.1±6.03 years, while it was 35.0±3.7 years in the control group. The mean expression of CT-1 in the CM subjects was 5.2±0.66, while it was 1.00±0.001 in the control group. A highly significant difference was observed in CT-1 expression in the CM group, and expression was significantly correlated with age and BMI in CM subjects.