Septic shock is a major cause of mortality in ICU patients, its pathophysiology is complex and not properly understood. Oxidative stress seems to be one of the most important mechanisms of shock progression to multiple organ failure. In the present pilot study, we have analysed eight oxidative-stress-related biomarkers in seven consecutive time points (i.e., the first seven days) in 21 septic shock patients admitted to the ICU. Our objective was to describe the kinetics of four biomarkers related to pro-oxidative processes (nitrite/nitrate, malondialdehyde, 8-oxo-2'-deoxyguanosine, soluble endoglin) compared to four biomarkers of antioxidant processes (the ferric reducing ability of plasma, superoxide dismutase, asymmetric dimethylarginine, mid-regional pro-adrenomedullin) and four inflammatory biomarkers (CRP, IL-6, IL-10 and neopterin). Furthermore, we analysed each biomarker's ability to predict mortality at the time of admission and 12 h after admission. Although a small number of study subjects were recruited, we have identified four promising molecules for further investigation: soluble endoglin, superoxide dismutase, asymmetric dimethylarginine and neopterin.

• Keywords
• antioxidant, asymmetric dimethylarginine, biomarker, neopterin, oxidative stress, sepsis, septic shock, soluble endoglin, superoxide dismutase,
• Publication type
• Journal Article MeSH

Endoglin is a 180 kDa transmembrane glycoprotein that was demonstrated to be present in two different endoglin forms, namely membrane endoglin (Eng) and soluble endoglin (sEng). Increased sEng levels in the circulation have been detected in atherosclerosis, arterial hypertension, and type II diabetes mellitus. Moreover, sEng was shown to aggravate endothelial dysfunction when combined with a high-fat diet, suggesting it might be a risk factor for the development of endothelial dysfunction in combination with other risk factors. Therefore, this study hypothesized that high sEng levels exposure for 12 months combined with aging (an essential risk factor of atherosclerosis development) would aggravate vascular function in mouse aorta. Male transgenic mice with high levels of human sEng in plasma (Sol-Eng+) and their age-matched male transgenic littermates that do not develop high soluble endoglin (Control) on a chow diet were used. The aging process was initiated to contribute to endothelial dysfunction/atherosclerosis development, and it lasted 12 months. Wire myograph analysis showed impairment contractility in the Sol-Eng+ group when compared to the control group after KCl and PGF2α administration. Endothelium-dependent responsiveness to Ach was not significantly different between these groups. Western blot analysis revealed significantly decreased protein expression of Eng, p-eNOS, and ID1 expression in the Sol-Eng+ group compared to the control group suggesting reduced Eng signaling. In conclusion, we demonstrated for the first time that long-term exposure to high levels of sEng during aging results in alteration of vasoconstriction properties of the aorta, reduced eNOS phosphorylation, decreased Eng expression, and altered Eng signaling. These findings suggest that sEng can be considered a risk factor for the development of vascular dysfunction during aging and a potential therapeutical target for pharmacological intervention.

• Keywords
• endoglin signaling, mice, soluble endoglin, vascular function,
• 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

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

Upon inflammation, monocyte-derived macrophages (MΦ) infiltrate blood vessels to regulate several processes involved in vascular pathophysiology. However, little is known about the mediators involved. Macrophage polarization is crucial for a fast and efficient initial response (GM-MΦ) and a good resolution (M-MΦ) of the inflammatory process. The functional activity of polarized MΦ is exerted mainly through their secretome, which can target other cell types, including endothelial cells. Endoglin (CD105) is a cell surface receptor expressed by endothelial cells and MΦ that is markedly upregulated in inflammation and critically involved in angiogenesis. In addition, a soluble form of endoglin with anti-angiogenic activity has been described in inflammation-associated pathologies. The aim of this work was to identify components of the MΦ secretome involved in the shedding of soluble endoglin. We find that the GM-MΦ secretome contains metalloprotease 12 (MMP-12), a GM-MΦ specific marker that may account for the anti-angiogenic activity of the GM-MΦ secretome. Cell surface endoglin is present in both GM-MΦ and M-MΦ, but soluble endoglin is only detected in GM-MΦ culture supernatants. Moreover, MMP-12 is responsible for the shedding of soluble endoglin in vitro and in vivo by targeting membrane-bound endoglin in both MΦ and endothelial cells. These data demonstrate a direct correlation between GM-MΦ polarization, MMP-12, and soluble endoglin expression and function. By targeting endothelial cells, MMP-12 may represent a novel mediator involved in vascular homeostasis.

• Keywords
• MMP-12, endoglin, endothelial cells, inflammation, macrophages, monocytes,
• MeSH
• Models, Biological MeSH
• Endoglin genetics   metabolism   MeSH
• Endothelial Cells metabolism   MeSH
• Gene Expression MeSH
• Granulocyte-Macrophage Colony-Stimulating Factor metabolism   MeSH
• Macrophage Colony-Stimulating Factor metabolism   MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Macrophages immunology   metabolism   MeSH
• Matrix Metalloproteinase 12 metabolism   MeSH
• Inflammation Mediators metabolism   MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• Disease Susceptibility MeSH
• Inflammation etiology   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Endoglin MeSH
• Granulocyte-Macrophage Colony-Stimulating Factor MeSH
• Macrophage Colony-Stimulating Factor MeSH
• Matrix Metalloproteinase 12 MeSH
• Inflammation Mediators MeSH

A soluble form of endoglin (sEng) released into the circulation was suggested to be a direct inducer of endothelial dysfunction, inflammation and contributed to the development of hypertension by interfering with TGF-β signaling in cardiovascular pathologies. In the present study, we assessed the hypothesis that high sEng level-induced hypertension via a possible sEng interference with TGF-β signaling pathways may result in inflammatory, structural or fibrotic changes in hearts of Sol-Eng+ mice (mice with high levels of soluble endoglin) fed either chow or high-fat diet. Female Sol-Eng+ mice and their age matched littermates with low plasma levels of sEng were fed either chow or high-fat diet (HFD). Heart samples were subsequently analyzed by histology, qRT-PCR and Western blot analysis. In this study, no differences in myocardial morphology/hypertrophy and possible fibrotic changes between Sol-Eng+ mice and control mice were detected on both chow and HFD. The presence of sEng did not significantly affect the expression of selected members of TGF-β signaling (membrane endoglin, TGFβRII, ALK-5, ALK-1, Id-1, PAI-1 and activated Smad proteins-pSmad 1,5 and pSmad 2,3), inflammation, heart remodeling (PDGFb, Col1A1) and endothelial dysfunction (VCAM-1, ICAM-1) in the hearts of Sol-Eng+ mice compared to control mice on both chow and high-fat diet. High levels of soluble endoglin did not affect microscopic structure (profibrotic and degenerative cardiomyocyte changes), and specific parts of TGF-β signaling, endothelial function and inflammation in the heart of Sol-Eng+ mice fed both chow diet or HFD. However, we cannot rule out a possibility that a long-term chronic exposure (9 months and more) to soluble endoglin alone or combined with other cardiovascular risk factors may contribute to alterations of heart function and structure in Sol-Eng+ mice, which is the topic in our lab in ongoing experiments.

• Keywords
• Heart, Inflammation, Mice, Soluble endoglin, TGF-β signaling,
• MeSH
• Endoglin biosynthesis   genetics   MeSH
• Hypertension blood   complications   MeSH
• Cardiomyopathy, Hypertrophic blood   etiology   pathology   MeSH
• Real-Time Polymerase Chain Reaction MeSH
• Disease Models, Animal MeSH
• Myocardium metabolism   pathology   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Oxidative Stress MeSH
• Gene Expression Regulation * MeSH
• RNA genetics   MeSH
• Signal Transduction MeSH
• Heart MeSH
• Gene Expression Profiling MeSH
• Transforming Growth Factor beta genetics   metabolism   MeSH
• Blotting, Western MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Endoglin MeSH
• Eng protein, mouse MeSH Browser
• RNA MeSH
• Transforming Growth Factor beta MeSH