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.

• Keywords
• Age-related macular degeneration, Alpha-2-macroglobulin, Rheopheresis, Soluble endoglin,
• 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
• Names of Substances
• Biomarkers * MeSH
• Endoglin * MeSH

Endoglin (Eng) is a co-receptor of the transforming growth factor β superfamily playing an important role in endothelial dysfunction. TRC105 (carotuximab) is a monoclonal antibody that blocks Eng and its downstream Smad signaling pathway. Here we have investigated for the first time the effects of TRC105 treatment on the development of endothelial dysfunction induced by 7-ketocholesterol (7K) or high glucose (HG), focusing on Eng expression, signaling, and function. In the hypercholesterolemia study, human aortic endothelial cells (HAoECs) were treated with TRC105 (300 μg/ml) for 1 h, followed by the addition of 7K (10 μg/ml) for another 12 h. In the hyperglycemia study, HAoECs were exposed to HG (45 mM) for 60 h, followed by the addition of TRC105 for another 12 h, and cells treated with 5mM glucose and 40 mM mannitol served as control. Protein levels, adhesion, and transmigration of monocytes were assessed by flow cytometry, mRNA expression was measured by qRT-PCR. 7K and HG treatment increased protein levels of NF-κB and Eng and adhesion and transmigration of monocytes through HAoECs monolayer. TRC105 pretreatment reduced the 7K- or HG-induced Eng protein levels and pSmad1/5 and pSmad2/3 signaling. Despite increased protein levels of P-selectin and VCAM-1, TRC105 mediated blockage of Eng prevented 7K- and HG-induced adhesion and transmigration of monocytes through endothelial monolayers. These results suggest that TRC105-mediated Eng blockage can counteract the hypercholesterolemia- and hyperglycemia-induced endothelial dysfunction in HAoECs, suggesting that Eng might be a potential therapeutic target in disorders associated with elevated cholesterol and glucose levels.

• Keywords
• 7-ketocholesterol, TRC105, endoglin, endothelial dysfunction, high glucose,
• Publication type
• Journal Article 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.

• Keywords
• Endoglin, Endothelial dysfunction, Hyperglycemia, Metabolic syndrome, Soluble endoglin,
• 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
• Names of Substances
• Biomarkers MeSH
• Endoglin MeSH
• Nitric Oxide Synthase Type III MeSH

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.

• Keywords
• Familial hypercholesterolemia, Inflammation, Lipids, Lipoprotein apheresis, Soluble endoglin,
• 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
• Names of Substances
• Biomarkers MeSH
• Endoglin MeSH
• Lipoproteins 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.

• Keywords
• FFC diet, NASH, bile acids, bile production, cholesterol, endoglin,
• 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
• Names of Substances
• Alkaline Phosphatase MeSH
• Aspartate Aminotransferases MeSH
• Biomarkers MeSH
• Cholesterol MeSH
• Endoglin MeSH
• Fructose MeSH
• Triglycerides MeSH

Soluble endoglin (sEng) released into the circulation was suggested to be related to cardiovascular based pathologies. It was demonstrated that a combination of high sEng levels and long-term exposure (six months) to high fat diet (HFD) resulted in aggravation of endothelial dysfunction in the aorta. Thus, in this study, we hypothesized that a similar experimental design would affect the heart morphology, TGFβ signaling, inflammation, fibrosis, oxidative stress and eNOS signaling in myocardium in transgenic mice overexpressing human sEng. Three-month-old female transgenic mice overexpressing human sEng in plasma (Sol-Eng+ high) and their age-matched littermates with low levels of human sEng (Sol-Eng+ low) were fed a high-fat diet containing 1.25% of cholesterol and 40% of fat for six months. A blood analysis was performed, and the heart samples were analyzed by qRT-PCR and Western blot. The results of this study showed no effects of sEng and HFD on myocardial morphology/hypertrophy/fibrosis. However, the expression of pSmad2/3 and p-eNOS was reduced in Sol-Eng+ high mice. On the other hand, sEng and HFD did not significantly affect the expression of selected members of TGFβ signaling (membrane endoglin, TGFβRII, ALK-5, ALK-1, Id-1, PAI-1), inflammation (VCAM-1, ICAM-1), oxidative stress (NQO1, HO-1) and heart remodeling (PDGFβ, COL1A1, β-MHC). In conclusion, the results of this study confirmed that sEng, even combined with a high-fat diet inducing hypercholesterolemia administered for six months, does not affect the structure of the heart with respect to hypertrophy, fibrosis, inflammation and oxidative stress. Interestingly, pSmad2/3/p-eNOS signaling was reduced in both the heart in this study and the aorta in the previous study, suggesting a possible alteration of NO metabolism caused by six months exposure to high sEng levels and HFD. Thus, we might conclude that sEng combined with a high-fat diet might be related to the alteration of NO production due to altered pSmad2/3/p-eNOS signaling in the heart and aorta.

• MeSH
• Aorta metabolism   pathology   MeSH
• Diet, High-Fat adverse effects   MeSH
• Endoglin * blood   metabolism   MeSH
• Fibrosis MeSH
• Hypercholesterolemia metabolism   MeSH
• Hypertrophy MeSH
• Myocardium metabolism   pathology   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Nitric Oxide metabolism   MeSH
• Oxidative Stress MeSH
• Inflammation MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Endoglin * MeSH
• ENG protein, human MeSH Browser
• Nitric Oxide MeSH

Increased levels of a soluble form of endoglin (sEng) circulating in plasma have been detected in various pathological conditions related to cardiovascular system. High concentration of sEng was also proposed to contribute to the development of endothelial dysfunction, but there is no direct evidence to support this hypothesis. Therefore, in the present work we analyzed whether high sEng levels induce endothelial dysfunction in aorta by using transgenic mice with high expression of human sEng. Transgenic mice with high expression of human sEng on CBAxC57Bl/6J background (Sol-Eng+) and age-matched transgenic littermates that do not develop high levels of human soluble endoglin (control animals in this study) on chow diet were used. As expected, male and female Sol-Eng+ transgenic mice showed higher levels of plasma concentrations of human sEng as well as increased blood arterial pressure, as compared to control animals. Functional analysis either in vivo or ex vivo in isolated aorta demonstrated that the endothelium-dependent vascular function was similar in Sol-Eng+ and control mice. In addition, Western blot analysis showed no differences between Sol-Eng+ and control mice in the protein expression levels of endoglin, endothelial NO-synthase (eNOS) and pro-inflammatory ICAM-1 and VCAM-1 from aorta. Our results demonstrate that high levels of soluble endoglin alone do not induce endothelial dysfunction in Sol-Eng+ mice. However, these data do not rule out the possibility that soluble endoglin might contribute to alteration of endothelial function in combination with other risk factors related to cardiovascular disorders.

• MeSH
• Aorta MeSH
• Arterial Pressure physiology   MeSH
• Vascular Cell Adhesion Molecule-1 metabolism   MeSH
• Endothelium, Vascular metabolism   pathology   MeSH
• Endoglin MeSH
• Intracellular Signaling Peptides and Proteins blood   MeSH
• Cardiovascular Diseases blood   metabolism   pathology   MeSH
• Intercellular Adhesion Molecule-1 metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Nitric Oxide Synthase Type III metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Vascular Cell Adhesion Molecule-1 MeSH
• Endoglin MeSH
• Eng protein, mouse MeSH Browser
• Intracellular Signaling Peptides and Proteins MeSH
• Intercellular Adhesion Molecule-1 MeSH
• Nos3 protein, mouse MeSH Browser
• Nitric Oxide Synthase Type III MeSH

BACKGROUND: Rheohemapheresis (RHF) is a method that can stop the activity of the dry form of age-related macular degeneration (AMD). The pathophysiologic mechanisms are not well understood, and the effects of the RHF procedures extend beyond the time of the individual procedures. PATIENTS AND METHODS: We present the data for 46 patients with AMD treated with a series of 8 rheohemapheretic procedures. Blood count parameters were measured before the first and the last procedures. The clinical effect was judged by changes in the drusenoid pigment epithelium detachment (DPED) area before and after the rheopheretic sessions. RESULTS: Rheopheresis caused a decrease in hemoglobin (P<0.001), a decrease in leukocytes (P<0.034), and an increase in platelets (P<0.005). We found a negative correlation between the amount of platelets and their volume (P<0.001, Pearson correlation coefficient: -0.509). We identified the platelet/MPV ratio as a good predictor of the clinical outcome. Patients with a platelet/MPV ratio greater than 21.5 (before the last rheopheresis) had a significantly better outcome (P=0.003, sensitivity of 76.9% and specificity of 80%). CONCLUSION: Several basic blood count parameters after RHF can be concluded to significantly change, with some of those changes correlating with the clinical results (reduction of the DPED area).

• MeSH
• Cytapheresis methods   MeSH
• Blood Cell Count MeSH
• Leukocytes cytology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Macular Degeneration therapy   MeSH
• Retinal Detachment diagnosis   pathology   therapy   MeSH
• Retinal Drusen complications   therapy   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Blood Platelets cytology   MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH