Liver sinusoidal endothelial inflammation/dysfunction and fibrosis are a crucial part of Metabolic Dysfunction Associated Steatohepatitis (MASH) development. TRC105 and M1043 are anti-endoglin (ENG) monoclonal antibodies that bind ENG. In this study, we hypothesized that treatment with anti-ENG antibodies would prevent the progression of LSECs inflammation and fibrosis in vivo and in vitro. MASH was induced in male C57BL/6 mice fed a choline-deficient L-amino acid-defined high-fat diet (CDAA-HFD) for 4 or 8 weeks. In the rescue study, mice were divided into three groups: a control group (chow diet), a MASH group (CDAA-HFD + IgG), and a rescue group (CDAA-HFD + M1043). Later, two groups received rat IgG1 (10 mg/kg) and M1043 (10 mg/kg). In in vitro experiments, inflammation was induced in human LSECs by ox-LDL (50 μg/mL) and treated with TRC105 (300 μg/mL). Liver sinusoidal endothelial inflammation/dysfunction in MASH animals was characterized by endothelial overexpression of ENG, VCAM-1, and ICAM-1 and reduced VE-cadherin and p-eNOS/eNOS expression. M1043 treatment prevented the overexpression of ENG, VCAM-1, and ICAM-1, the progression of liver fibrosis, and the increase of liver-to-body weight ratio. In vitro experiments with TRC105 confirmed the prevention of LSECs inflammation development by reduced ENG and VCAM-1 expression, as well as decreased THP-1 monocytic cell adhesion in ox-LDL activated LSECs. In conclusion, we demonstrate that anti-ENG antibody treatment can prevent LSECs inflammation and fibrosis progression in a MASH animal model and LSECs inflammation in vitro. Thus, we propose directly targeted ENG may represent a promising pharmacological approach for addressing LSECs inflammation and liver fibrosis.

• MeSH
• Diet, High-Fat adverse effects   MeSH
• Endoglin * metabolism   antagonists & inhibitors   MeSH
• Endothelial Cells drug effects   metabolism   pathology   MeSH
• Liver Cirrhosis * prevention & control   pathology   drug therapy   metabolism   MeSH
• Liver * pathology   drug effects   metabolism   MeSH
• Rats MeSH
• Humans MeSH
• Antibodies, Monoclonal * pharmacology   MeSH
• Mice, Inbred C57BL * MeSH
• Mice MeSH
• Non-alcoholic Fatty Liver Disease drug therapy   prevention & control   pathology   metabolism   MeSH
• Disease Progression MeSH
• Inflammation * pathology   drug therapy   metabolism   prevention & control   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Liver sinusoidal endothelial cells (LSECs) play a crucial role in regulating the hepatic function. Endoglin (ENG), a transmembrane glycoprotein, was shown to be related to the development of endothelial dysfunction. In this study, we hypothesized the relationship between changes in ENG expression and markers of liver sinusoidal endothelial dysfunction (LSED) during liver impairment. Male C57BL/6J mice aged 9-12 weeks were fed with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet (intrahepatic cholestasis) or choline-deficient l-amino acid defined high-fat diet (CDAA-HFD) (non-alcoholic steatohepatitis (NASH)). Significant increases in liver enzymes, fibrosis, and inflammation biomarkers were observed in both cholestasis and NASH. Decreased p-eNOS/eNOS and VE-cadherin protein expression and a significant increase in VCAM-1 and ICAM-1 expression were detected, indicating LSED in both mouse models of liver damage. A significant reduction of ENG in the DDC-fed mice, while a significant increase of ENG in the CDAA-HFD group was observed. Both DDC and CDAA-HFD-fed mice showed a significant increase in MMP-14 protein expression, which is related to significantly increased levels of soluble endoglin (sENG) in the plasma. In conclusion, we demonstrated that intrahepatic cholestasis and NASH result in an altered ENG expression, predominantly in LSECs, suggesting a critical role of ENG expression for the proper function of liver sinusoids. Both pathologies resulted in elevated sENG levels, cleaved by MMP-14 expressed predominantly from LSECs, indicating sENG as a liver injury biomarker.

• MeSH
• Acetamides * MeSH
• Diet, High-Fat adverse effects   MeSH
• Endoglin metabolism   MeSH
• Endothelial Cells metabolism   MeSH
• Cholestasis, Intrahepatic * MeSH
• Matrix Metalloproteinase 14 MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Non-alcoholic Fatty Liver Disease * pathology   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Age-related macular degeneration (AMD) is a progressive chronic disease causing visual impairment or central vision loss in the elderly. We hypothesized that successful rheopheresis would be associated with positive changes in soluble endoglin (sENG), PSCK9, alpha-2-macroglobulin (A2M), and hs-CRP levels. 31 elderly patients with the dry form of AMD, treated with rheopheresis with a follow-up period of at least 5 years and an average age of 68 ± 4 years, were evaluated. Each treated patient received a series of 8 procedures in 10 weeks and, after the 2-year period, another 2 procedures within 1 week. Then, the patients were followed up every 6 months and divided into the successfully treated and therapeutic failure group according to best-corrected visual acuity (BCVA), size of the drusen area, and the drusenoid pigment epithelium detachment (DPED). Based on the ophthalmological assessment, rheopheresis treatment was successful in 73% of AMD patients. The therapy was associated with a significant decrease in total cholesterol, LDL-C, HDL-C, apoprotein B, lipoprotein (a) levels, and rheologically important parameters, irrespective of the therapy's success or failure. The success of rheopheresis therapy was exclusively related to a significant decrease in sENG and A2M levels. Over the long term, rheopheresis prevented the decline of BCVA, reduced the DPED and area of macular drusen, and improved the preservation of an intact photoreceptor ellipsoid zone in most patients. Moreover, we showed for the first time that sENG and A2M could be potentially sensitive biomarkers of successful rheopheresis procedure, irrespective of lipid parameters changes.

• MeSH
• Biomarkers * blood   MeSH
• Endoglin * blood   MeSH
• Middle Aged MeSH
• Humans MeSH
• Macular Degeneration * therapy   blood   MeSH
• Aged MeSH
• Treatment Outcome MeSH
• Visual Acuity MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Elevated preoperative plasma level of endoglin has been associated with worse oncologic outcomes in various malignancies. The present large-scale study aimed to determine the predictive and prognostic values of preoperative endoglin with regard to clinicopathologic and survival outcomes in patients treated with radical cystectomy (RC) for nonmetastatic urothelial carcinoma of the bladder (UCB). We prospectively collected preoperative blood samples from 1036 consecutive patients treated with RC for UCB. Logistic and Cox regression analyses were undertaken to assess the correlation of endoglin levels with pathologic and survival outcomes, respectively. The AUC and C-index were used to assess the discrimination. Patients with adverse pathologic features had significantly higher median preoperative endoglin plasma levels than their counterparts. Higher preoperative endoglin level was independently associated with an increased risk for lymph node metastasis, ≥pT3 disease, and nonorgan confined disease (NOCD; all p < 0.001). Plasma endoglin level was also independently associated with cancer-specific and overall survival in both pre- and postoperative models (all p < 0.05), as well as with recurrence-free survival (RFS) in the preoperative model (p < 0.001). The addition of endoglin to the preoperative standard model improved its discrimination for prediction of lymph node metastasis, ≥pT3 disease, NOCD, and RFS (differential increases in C-indices: 10%, 5%, 5.8%, and 4%, respectively). Preoperative plasma endoglin is associated with features of biologically and clinically aggressive UCB as well as survival outcomes. Therefore, it seems to hold the potential of identifying UCB patients who may benefit from intensified therapy in addition to RC such as extended lymphadenectomy or/and preoperative systemic therapy.

• MeSH
• Survival Analysis MeSH
• Cystectomy MeSH
• Endoglin blood   MeSH
• Carcinoma, Transitional Cell blood   pathology   surgery   MeSH
• Middle Aged MeSH
• Humans MeSH
• Lymph Node Excision MeSH
• Biomarkers, Tumor blood   MeSH
• Urinary Bladder Neoplasms blood   pathology   surgery   MeSH
• Preoperative Period MeSH
• Prognosis MeSH
• Prospective Studies MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Aged MeSH
• Neoplasm Staging MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Membrane endoglin (Eng, CD105) is a transmembrane glycoprotein essential for the proper function of vascular endothelium. It might be cleaved by matrix metalloproteinases to form soluble endoglin (sEng), which is released into the circulation. Metabolic syndrome comprises conditions/symptoms that usually coincide (endothelial dysfunction, arterial hypertension, hyperglycemia, obesity-related insulin resistance, and hypercholesterolemia), and are considered risk factors for cardiometabolic disorders such as atherosclerosis, type II diabetes mellitus, and liver disorders. The purpose of this review is to highlight current knowledge about the role of Eng and sEng in the disorders mentioned above, in vivo and in vitro extent, where we can find a wide range of contradictory results. We propose that reduced Eng expression is a hallmark of endothelial dysfunction development in chronic pathologies related to metabolic syndrome. Eng expression is also essential for leukocyte transmigration and acute inflammation, suggesting that Eng is crucial for the regulation of endothelial function during the acute phase of vascular defense reaction to harmful conditions. sEng was shown to be a circulating biomarker of preeclampsia, and we propose that it might be a biomarker of metabolic syndrome-related symptoms and pathologies, including hypercholesterolemia, hyperglycemia, arterial hypertension, and diabetes mellitus as well, despite the fact that some contradictory findings have been reported. Besides, sEng can participate in the development of endothelial dysfunction and promote the development of arterial hypertension, suggesting that high levels of sEng promote metabolic syndrome symptoms and complications. Therefore, we suggest that the treatment of metabolic syndrome should take into account the importance of Eng in the endothelial function and levels of sEng as a biomarker and risk factor of related pathologies.

• MeSH
• Atherosclerosis metabolism   pathology   MeSH
• Biomarkers metabolism   MeSH
• Cell Membrane metabolism   MeSH
• Diabetes Mellitus, Type 2 metabolism   pathology   MeSH
• Endoglin chemistry   metabolism   MeSH
• Gene Expression MeSH
• Cardiovascular Diseases metabolism   pathology   MeSH
• Humans MeSH
• Metabolic Syndrome metabolism   pathology   MeSH
• Nitric Oxide Synthase Type III metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Solubilní endoglin (Sol-Eng), je uvolňován do krve při závažných patologických stavech spojených, hypercholesterolemií, diabetes mellitus (DM) typu 2 a zánětem. V tomto grantovém projektu navrhujeme prospektivní randomizovanou studii se 114 pacienty (90 s DM 2. typu a 14 s Familiární hypercholesterolemií). Cílem projektu je zjistit zda změny sérových hladin Sol-Eng reflektuji změny zánětlivých markerů v séru, markerů endotelové dysfunkce v séru, aterogeneze (intima media thickness v arteria carotis) a markerů kompenzace diabetes mellitus 2 typu po podávání statinů u pacientů s diabetem nebo u pacientů s Familiární hypercholesterolemií (homozygoti versus heterozygoti). Výzkum logicky podporuje experimentální část, která je zaměřena na studium vlivu Sol-Eng na jaterní tkáň zejména na metabolismus cholesterolu, žlučových kyselin, zánětlivé markery a profibrotické změny. Výsledky tohoto projektu by tedy mohly přispět k popisu chování Sol-Eng v patogenezi, zejména však při terapii (statiny) a komplikacích diabetes mellitus 2 typu ve vztahu k aterogenezi a kompenzaci diabetu.; Soluble endoglin (Sol-Eng) levels are increased in blood during serious pathological conditions related to hypercholesterolemia, diabetes mellitus (DM), and inflammation. This grant project brings a prospective randomized study with 104 patients (90 with type 2 DM and 14 with Familial hypercholesterolemia). We aim to elucidate whether Sol-Eng changes are related to atherogenic changes in the vessels (intima media thickness), the changes of markers of inflammation and type 2 diabetes mellitus compensation before and after statin treatment. In addition, we would like to focus on the possible differences in Sol-Eng levels and markers of inflammation, endothelial dysfunction in homozygous and heterozygous patients diagnosed with Familial hypercholesterolemia. Supporting experimental study should give us more information regarding the role of Sol-Eng as potential inducer of pathological changes in liver. The whole grant project should therefore help us to understand the role of Sol-Eng in type 2 diabetes mellitus and hypercholesterolemia associated pathologies.

• MeSH
• Atherosclerosis MeSH
• Biomarkers MeSH
• Diabetes Mellitus, Type 2 drug therapy   MeSH
• Endoglin metabolism   therapeutic use   MeSH
• Hypercholesterolemia drug therapy   MeSH
• Diabetes Complications MeSH
• Humans MeSH
• Prospective Studies MeSH
• Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use   MeSH
• Treatment Outcome MeSH
• Inflammation MeSH
• Check Tag
• Humans MeSH
• Publication type
• Randomized Controlled Trial MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• farmacie a farmakologie
• diabetologie
• vnitřní lékařství
• NML Publication type
• závěrečné zprávy o řešení grantu AZV MZ ČR

BACKGROUND: Lipoprotein apheresis (LA) is considered as an add-on therapy for patients with familial hypercholesterolemia (FH). We aimed to analyze the data collected in the last 15 years from FH patients treated with LA, to elucidate the benefit of this procedure with respect to plasma lipids, biomarkers of inflammation, and endothelial dysfunction and soluble endoglin. RESULTS: 14 patients (10 heterozygous FH patients (HeFH), 4 homozygous FH patients (HoFH)) were treated by long-term lipoprotein apheresis. Lipid levels were examined, and ELISA detected biomarkers of inflammation and soluble endoglin. Paired tests were used for intergroup comparisons, and a linear regression model served to estimate the influence of the number of days patients were treated with LA on the studied parameters. LA treatment was associated with a significant decrease of total cholesterol (TC), LDL-C, HDL-C, and apoB, in both HeFH and HoFH patients, after single apheresis and in a long-term period during the monitored interval of 15 years. Biomarkers of inflammation and endothelial dysfunction were reduced for soluble endoglin, hsCRP, and MCP-1, and sP-selectin after each procedure in some HeFH and HoFH patients. CONCLUSIONS: LA treatment up to 15 years, reduced cholesterol levels, levels of biomarkers related to endothelial dysfunction, and inflammation not only after each procedure but also in the long-term evaluation in FH patients. We propose that long-term LA treatment improves lipid profile and endothelial dysfunction in familial hypercholesterolemia patients, suggesting a promising improvement in cardiovascular prognosis in most FH patients.

• MeSH
• Biomarkers MeSH
• Endoglin MeSH
• Hyperlipoproteinemia Type II * genetics   therapy   MeSH
• Humans MeSH
• Lipoproteins MeSH
• Blood Component Removal * MeSH
• Inflammation MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

• MeSH
• Endoglin * MeSH
• Humans MeSH
• Metabolic Syndrome * MeSH
• Check Tag
• Humans MeSH

Nonalcoholic steatohepatitis (NASH) is characterized by hepatic steatosis with inflammation and fibrosis. Membrane endoglin (Eng) expression is shown to participate in fibrosis, and plasma concentrations of soluble endoglin (sEng) are increased in patients with hypercholesterolemia and type 2 diabetes mellitus. We hypothesize that NASH increases both hepatic Eng expression and sEng in blood and that high levels of sEng modulate cholesterol and bile acid (BA) metabolism and affect NASH progression. Three-month-old transgenic male mice overexpressing human sEng and their wild type littermates are fed for six months with either a high-saturated fat, high-fructose high-cholesterol (FFC) diet or a chow diet. Evaluation of NASH, Liquid chromatography-mass spectrometry (LC/MS) analysis of BA, hepatic expression of Eng, inflammation, fibrosis markers, enzymes and transporters involved in hepatic cholesterol and BA metabolism are assessed using Real-Time Quantitative Reverse Transcription Polymerase Chain reaction (qRT-PCR) and Western blot. The FFC diet significantly increases mouse sEng levels and increases hepatic expression of Eng. High levels of human sEng results in increased hepatic deposition of cholesterol due to reduced conversion into BA, as well as redirects the metabolism of triglycerides (TAG) to its accumulation in the liver, via reduced TAG elimination by β-oxidation combined with reduced hepatic efflux. We propose that sEng might be a biomarker of NASH development, and the presence of high levels of sEng might support NASH aggravation by impairing the essential defensive mechanism protecting NASH liver against excessive TAG and cholesterol accumulation, suggesting the importance of high sEng levels in patients prone to develop NASH.

• MeSH
• Alkaline Phosphatase metabolism   MeSH
• Aspartate Aminotransferases metabolism   MeSH
• Biomarkers blood   metabolism   MeSH
• Models, Biological MeSH
• Cholesterol blood   metabolism   MeSH
• Diet, High-Fat MeSH
• Endoglin blood   metabolism   MeSH
• Fructose MeSH
• Liver Cirrhosis blood   complications   pathology   MeSH
• Liver metabolism   pathology   MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• Non-alcoholic Fatty Liver Disease blood   complications   metabolism   MeSH
• Oxidative Stress MeSH
• Solubility MeSH
• Triglycerides metabolism   MeSH
• Inflammation pathology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Pulsatile Carmat bioprosthetic total artificial heart (C-TAH) is designed to be implanted in patients with biventricular end-stage heart failure. Since flow variation might contribute to endothelial dysfunction, we explored circulating endothelial biomarkers after C-TAH implantation in seven patients and compared the manual and autoregulated mode. Markers of endothelial dysfunction and regeneration were compared before and during a 6- to 9-month follow-up after implantation. The follow-up was divided into three periods (< 3, 3-6, and > 6 months) and used to estimate the temporal trends during the study period. A linear mixed model was used to analyze repeated measures and association between tested parameters according to the mode of C-TAH and the time. Relevance of soluble endoglin (sEndoglin) level increase has been tested on differentiation and migration potential of human vasculogenic progenitor cells (endothelial colony forming cells [ECFCs]). Normal sEndoglin and soluble endothelial protein C receptor (sEPCR) levels were found in patients after implantation with autoregulated C-TAH, whereas they significantly increased in the manual mode, as compared with pretransplant values (p = 0.005 and 0.001, respectively). In the autoregulated mode, a significant increase in the mobilization of cytokine stromal cell-derived factor 1 was found (p = 0.03). After adjustment on the mode of C-TAH, creatinine or C-reactive protein level, sEndoglin, and sEPCR, were found significantly associated with plasma total protein levels. Moreover, a significant decrease in pseudotubes formation and migration ability was observed in vitro in ECFCs receiving sEndoglin activation. Our combined analysis of endothelial biomarkers confirms the favorable impact of blood flow variation achieved with autoregulation in patients implanted with the bioprosthetic total artificial heart.

• MeSH
• Biomarkers analysis   MeSH
• Bioprosthesis * MeSH
• Endoglin analysis   MeSH
• Endothelium pathology   MeSH
• Endothelial Protein C Receptor analysis   MeSH
• Homeostasis MeSH
• Humans MeSH
• Follow-Up Studies MeSH
• Aged MeSH
• Heart Failure therapy   MeSH
• Heart, Artificial * MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH