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International Journal of Molecular... Aug 2023The early identification of women with an increased risk of preeclampsia (PE) is desirable, but apart from soluble fms-like tyrosine kinase-1 (sFlt-1), few biomarkers... (Meta-Analysis)
Meta-Analysis Review
The early identification of women with an increased risk of preeclampsia (PE) is desirable, but apart from soluble fms-like tyrosine kinase-1 (sFlt-1), few biomarkers have previously been identified as relevant for predicting preeclampsia. Since kinases and phosphatases regulate critical biological processes and previous evidence suggests a potential role of these molecules in preeclampsia, we performed this systematic review and metanalysis. The objective was to determine if there are kinases and phosphatases whose serum levels are different between women with and without PE, being relevant biomarkers of PE. We followed the recommendations of Cochrane and the Preferred Reported Items for Systematic Reviews and Metanalysis (PRISMA) to perform this study. The MESH terms preeclampsia, kinases, phosphatases, angiopoietins, soluble tyrosine protein kinase receptor (sTIE2), and cellular-mesenchymal-epithelial transition factor (c-MET) were combined to find relevant articles in the PubMed, PROSPERO, and Cochrane databases. Then, a qualitative and quantitative analysis was performed in R Studio software. From 580 abstracts identified, 37 were included in the final analysis, which comprised 24,211 pregnant women (2879 with PE and 21,332 women without PE [HP]. The pooled analysis showed that serum creatine kinase (CK) (SMD: 2.43, CI 95% 0.25-4.62) was significantly higher in PE, whereas sTIE2 and anti-angiogenic factor soluble c-Met (sMet)were significantly lower in PE than in HP (SMD: -0.23, CI95% -0.37 to -0.09; and SMD:0.24, CI95% 0.01-0.47, respectively). Adenosine monophosphate-activated protein kinase (AMPK), angiopoietin-1 (ANG-1), angiopoietin-2 (ANG-2), the ratio angiopoietin-1/angiopoietin-2, acid phosphatase, and alkaline phosphatase were not different between women with PE and HP. In summary CK, sTIE2, and c-MET are relevant biomarkers of PE. It is desirable to incorporate them into current models for PE prediction to evaluate their utility as biomarkers.
Topics: Pregnancy; Female; Humans; Phosphoric Monoester Hydrolases; Angiopoietin-1; Angiopoietin-2; Pre-Eclampsia; Antibodies; Receptor, trkA
PubMed: 37629025
DOI: 10.3390/ijms241612842 -
Scientific Reports Oct 2023Early detection of atrial fibrillation (AF) enables initiation of anticoagulation and early rhythm control therapy to reduce stroke, cardiovascular death, and heart... (Observational Study)
Observational Study
Early detection of atrial fibrillation (AF) enables initiation of anticoagulation and early rhythm control therapy to reduce stroke, cardiovascular death, and heart failure. In a cross-sectional, observational study, we aimed to identify a combination of circulating biomolecules reflecting different biological processes to detect prevalent AF in patients with cardiovascular conditions presenting to hospital. Twelve biomarkers identified by reviewing literature and patents were quantified on a high-precision, high-throughput platform in 1485 consecutive patients with cardiovascular conditions (median age 69 years [Q1, Q3 60, 78]; 60% male). Patients had either known AF (45%) or AF ruled out by 7-day ECG-monitoring. Logistic regression with backward elimination and a neural network approach considering 7 key clinical characteristics and 12 biomarker concentrations were applied to a randomly sampled discovery cohort (n = 933) and validated in the remaining patients (n = 552). In addition to age, sex, and body mass index (BMI), BMP10, ANGPT2, and FGF23 identified patients with prevalent AF (AUC 0.743 [95% CI 0.712, 0.775]). These circulating biomolecules represent distinct pathways associated with atrial cardiomyopathy and AF. Neural networks identified the same variables as the regression-based approach. The validation using regression yielded an AUC of 0.719 (95% CI 0.677, 0.762), corroborated using deep neural networks (AUC 0.784 [95% CI 0.745, 0.822]). Age, sex, BMI and three circulating biomolecules (BMP10, ANGPT2, FGF23) are associated with prevalent AF in unselected patients presenting to hospital. Findings should be externally validated. Results suggest that age and different disease processes approximated by these three biomolecules contribute to AF in patients. Our findings have the potential to improve screening programs for AF after external validation.
Topics: Humans; Male; Aged; Female; Atrial Fibrillation; Angiopoietin-2; Cross-Sectional Studies; Biomarkers; Stroke; Risk Factors; Bone Morphogenetic Proteins
PubMed: 37798357
DOI: 10.1038/s41598-023-42331-7 -
Growth Factors (Chur, Switzerland) 2021"Quantile-dependent expressivity" occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g. growth factor concentration) is high or low...
BACKGROUND
"Quantile-dependent expressivity" occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g. growth factor concentration) is high or low relative to its distribution.
METHODS
Quantile-regression analysis was applied to family sets from the Framingham Heart Study to determine whether the heritability () of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), angiopoietin-2, and angiopoietin-2 (sTie-2) and VEGFR1 (sFlt-1) receptor concentrations were quantile-specific.
RESULTS
Quantile-specific (±SE) increased with increasing percentiles of the age- and sex-adjusted VEGF (<10), HGF (=0.0004), angiopoietin-2 (=0.0002), sTie-2 (=1.2 × 10), and sFlt-1 distributions (=0.04).
CONCLUSION
Heritabilities of VEGF, HGF, angiopoitein-2, sTie-2 and sFlt-1 concentrations are quantile dependent. This may explain reported interactions of genetic loci (rs10738760, rs9472159, rs833061, rs3025039, rs2280789, rs1570360, rs2010963) with metabolic syndrome, diet, recurrent miscarriage, hepatocellular carcinoma, erysipelas, diabetic retinopathy, and bevacizumab treatment in their effect on VEGF concentrations.
Topics: Angiopoietin-2; Phenotype; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1
PubMed: 35312415
DOI: 10.1080/08977194.2022.2049261 -
Journal of the American Heart... Nov 2021Background Individuals infected with HIV have an increased risk of developing cardiovascular disease; yet, the underlying mechanisms remain unknown. Recent evidence has... (Observational Study)
Observational Study
Background Individuals infected with HIV have an increased risk of developing cardiovascular disease; yet, the underlying mechanisms remain unknown. Recent evidence has implicated the Tie-2 tyrosine kinase receptor system and its associated ligands ANG1 (angiopoietin 1) and ANG2 (angiopoietin 2) in maintaining vascular homeostasis. In the general population, lower ANG1 levels and higher ANG2 levels are strongly correlated with the development of cardiovascular disease. In this study, we aim to investigate the associations of HIV infection with angiopoietin levels and endothelial dysfunction. Methods and Results In this cross-sectional study, we compared measures of ANG1, ANG2, and endothelial dysfunction using flow-mediated vasodilation of the brachial artery in 39 untreated subjects infected with HIV, 47 treated subjects infected with HIV, and 46 uninfected subjects from the SCOPE (Observational Study of the Consequences of the Protease Inhibitor Era) cohort. Compared with uninfected controls, treated individuals infected with HIV had 53.1% lower mean ANG1 levels (<0.01) and similar ANG2 levels. On the other hand, untreated individuals infected with HIV had similar ANG1 levels, and 29.2% had higher ANG2 levels (<0.01) compared with uninfected controls. When compared with individuals with untreated HIV infection, those with treated HIV infection had 56% lower ANG1 levels (<0.01) and 22% lower ANG2 levels (<0.01).Both treated and untreated HIV infection were associated with significant impairment in hyperemic velocity, a key measure of microvascular dysfunction (median 61 versus 72 cm/s, <0.01), compared with uninfected controls (median 73 cm/s). This difference persisted after adjustment for ANG1 and ANG2 levels. Interestingly, when compared with untreated individuals infected with HIV, treated individuals infected with HIV had worse hyperemic velocity (-12.35 cm/s, =0.05). In contrast, HIV status, ANG1 levels, and ANG2 levels were not associated with macrovascular dysfunction as measured by flow-mediated dilatation and brachial artery diameter, 2 other measures of vascular homeostasis. Conclusions HIV infection affects the balance between levels of ANG1 and ANG2 and may disturb endothelial homeostasis through disruption of vascular homeostasis. Individuals with treated HIV had decreased ANG1 levels and similar ANG2 levels, whereas individuals with untreated HIV had similar ANG1 levels and increased ANG2 levels, suggesting that treatment status may alter the balance between ANG1 and ANG2. HIV also promotes endothelial dysfunction via impairment of microvascular dysfunction, independent of the Tie-2 receptor system; the finding of worse microvascular dysfunction in the setting of treated HIV infection may reflect the impact of viral persistence on the microvasculature or toxicities of specific antiretroviral regimens. Further research to clarify the mechanism of HIV-mediated endothelial dysfunction is necessary to advance treatment of cardiovascular complications of HIV infection.
Topics: Angiopoietin-1; Angiopoietin-2; Cardiovascular Diseases; Cross-Sectional Studies; HIV Infections; HIV-1; Humans; Receptor, TIE-2
PubMed: 34726064
DOI: 10.1161/JAHA.121.021397 -
Transactions of the American Clinical... 2023Microvascular endothelial activation/dysfunction has emerged as an important mechanistic pathophysiological process in the development of morbidity and mortality in...
Microvascular endothelial activation/dysfunction has emerged as an important mechanistic pathophysiological process in the development of morbidity and mortality in life-threatening infections. The angiopoietin-Tie2 system plays an integral role in the regulation of microvascular endothelial integrity. Angiopoietin-1 (Ang-1), produced by platelets and pericytes, is the cognate agonistic ligand for Tie2, promoting endothelial quiescence and inhibiting microvascular leak. Angiopoietin-2 (Ang-2), released from activated endothelial cells in Weibel-Palade bodies, competes with Ang-1 for binding to Tie-2, thereby promoting endothelial activation/dysfunction and microvascular leak. In healthy homeostasis, levels of Ang-1 far exceed Ang-2 in circulating serum/plasma. In diseases associated with systemic inflammation, Ang-1 falls and Ang-2 rises (i.e., Ang-1/2 dysregulation). Our research has shown that Ang-1/2 dysregulation is a prominent feature in a number of life-threatening infections and critical illnesses, including sepsis, cerebral malaria, COVID-19, streptococcal toxic shock syndrome (STSS), hemolytic-uremic syndrome (HUS), dengue, and CAR T-cell-associated neurotoxicity. Further work has implicated Ang-1/2 dysregulation in the development of end-organ injury, including acute lung injury/ARDS, acute kidney injury (AKI), and blood-brain-barrier (BBB) breakdown. Current studies are focused in three areas: (a) translation of Ang-1 and -2 as clinically informative prognostic and "theranostic" biomarkers in critically ill individuals; (b) incorporation of Ang-1/2 assays in a point of care device for clinical triage decision making; and (c) development of an engineered Ang-1 super agonist nanoparticle as a novel pathogen-agnostic therapeutic to prevent and/or mitigate end-organ dysfunction in individuals with life-threatening infections and critical illnesses associated with systemic inflammation.
Topics: Humans; Angiopoietins; COVID-19; Critical Illness; Endothelial Cells; Inflammation
PubMed: 37701588
DOI: No ID Found -
Frontiers in Endocrinology 2021Diabetic cardiomyopathy (DbCM) is characterized by initial impairment of left ventricular relaxation followed by contractile dysfunction. Despite intensive research, the...
BACKGROUND
Diabetic cardiomyopathy (DbCM) is characterized by initial impairment of left ventricular relaxation followed by contractile dysfunction. Despite intensive research, the exact mechanism remains so far unsolved.
METHODS
We constructed weighted gene co-expression network analysis (WGCNA) to screen gene modules that were closely related with DbCM based on the GSE5606 dataset, which contained expression data of the cardiac left ventricle in a rodent model of streptozotocin (STZ)-induced DbCM. Then, the most related hub gene, angiopoietin-like 4 (ANGPTL4), was selected for functional and assays. In our experiments, STZ-induced diabetic mice (C57BL/6J) and human cardiomyocytes (AC16) were used to study the functional roles and potential mechanisms of ANGPTL4 in DbCM.
RESULTS
WGCNA analysis revealed the yellow and green modules were most correlated with DbCM, and identified ANGPTL4 as one of the most significantly upregulated hub genes (, , , , and ). Consistent with the bioinformatic analysis, the amount of ANGPTL4 was significantly upregulated in diabetic mouse heart. DbCM group, compared with the control group, had increased phosphorylation of focal adhesion kinase (FAK), reduced SIRT3 expression, increased SOD2 acetylation, upregulated NADPH oxidase activation, elevated reactive oxygen species (ROS) produciton, and enhanced apoptosis in the diabetic mouse heart. Moreover, ANGPTL4 induced apoptosis FAK/SIRT3/ROS pathway in human cardiomyocytes (AC16) under high glucose condition These effects were abrogated by treatment of two independent siRNA for ANGPTL4, whereas exogenous recombinant ANGPLT4 protein treatment exacerbated those effects in AC16.
CONCLUSION
We found , , , , and were significantly increased in diabetic heart. ANGPTL4 could promote cardiac apoptosis a FAK/SIRT3/ROS dependent signaling pathway in DbCM.
Topics: Angiopoietin-Like Protein 4; Animals; Apoptosis; Biomarkers; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Focal Adhesion Protein-Tyrosine Kinases; Humans; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; Oxidative Stress; Prognosis; Reactive Oxygen Species; Sirtuin 3
PubMed: 34616362
DOI: 10.3389/fendo.2021.705154 -
Biomedicines May 2022Very preterm infants are exposed to prenatal inflammatory processes and early postnatal hemodynamic and respiratory complications, but limited data are available about...
Very preterm infants are exposed to prenatal inflammatory processes and early postnatal hemodynamic and respiratory complications, but limited data are available about the endothelial effect of these conditions. The present pilot study investigates the perinatal endothelial phenotype in very preterm infants (VPIs) and explores its predictive value on neonatal mortality and hemodynamic and respiratory complications. Angiopoietin 1 (Ang-1), Ang-2, E-selectin, vascular adhesion molecule 1 (VCAM-1), tissue factor (TF), and endothelin 1 (ET-1) concentrations were tested in first (T1), 3rd (T2), and 7-10th (T3) day of life in 20 VPIs using Luminex technology and compared with 14 healthy full-term infants (FTIs). Compared to FTIs, VPIs had lower Ang-1 at T1 and T2; higher Ang-2 at T1, T2, and T3; higher Ang-2/Ang-1 ratio at T1, T2, and T3; lower E-selectin at T1, T2, and T3; higher VCAM-1 at T1; higher TF at T2. No differences in concentrations were found in neonatal deaths. VPIs with hemodynamic or respiratory complications had higher Ang-2 at T3. Perinatal low Ang-1 and high Ang-2 associated with high VCAM-1 and TF in VPIs suggest a proinflammatory endothelial phenotype, resulting from the synergy of a pathological prenatal inheritance and a premature extrauterine transition.
PubMed: 35625922
DOI: 10.3390/biomedicines10051185 -
Cells Oct 2022Pericytes (PCs), as a central component of the neurovascular unit, contribute to the regenerative potential of the central nervous system (CNS) and peripheral nervous... (Review)
Review
Pericytes (PCs), as a central component of the neurovascular unit, contribute to the regenerative potential of the central nervous system (CNS) and peripheral nervous system (PNS) by virtue of their role in blood flow regulation, angiogenesis, maintenance of the BBB, neurogenesis, and neuroprotection. Emerging evidence indicates that PCs also have a role in mediating cell-to-cell communication through the secretion of extracellular vesicles (EVs). Extracellular vesicles are cell-derived, micro- to nano-sized vesicles that transport cell constituents such as proteins, nucleic acids, and lipids from a parent originating cell to a recipient cell. PC-derived EVs (PC-EVs) play a crucial homeostatic role in neurovascular disease, as they promote angiogenesis, maintain the integrity of the blood-tissue barrier, and provide neuroprotection. The cargo carried by PC-EVs includes growth factors such as endothelial growth factor (VEGF), connecting tissue growth factors (CTGFs), fibroblast growth factors, angiopoietin 1, and neurotrophic growth factors such as brain-derived neurotrophic growth factor (BDNF), neuron growth factor (NGF), and glial-derived neurotrophic factor (GDNF), as well as cytokines such as interleukin (IL)-6, IL-8, IL-10, and MCP-1. The PC-EVs also carry miRNA and circular RNA linked to neurovascular health and the progression of several vascular and neuronal diseases. Therapeutic strategies employing PC-EVs have potential in the treatment of vascular and neurodegenerative diseases. This review discusses current research on the characteristic features of EVs secreted by PCs and their role in neuronal and vascular health and disease.
Topics: Angiopoietin-1; Brain-Derived Neurotrophic Factor; Cytokines; Endothelial Growth Factors; Extracellular Vesicles; Fibroblast Growth Factors; Glial Cell Line-Derived Neurotrophic Factor; Interleukin-10; Interleukin-8; Lipids; MicroRNAs; Nerve Growth Factor; Pericytes; RNA, Circular; Vascular Endothelial Growth Factor A
PubMed: 36231071
DOI: 10.3390/cells11193108 -
Cancer Research Jun 2023T-cell position in the tumor microenvironment determines the probability of target encounter and tumor killing. CD8+ T-cell exclusion from the tumor parenchyma is...
UNLABELLED
T-cell position in the tumor microenvironment determines the probability of target encounter and tumor killing. CD8+ T-cell exclusion from the tumor parenchyma is associated with poor response to immunotherapy, and yet the biology that underpins this distinct pattern remains unclear. Here we show that the vascular destabilizing factor angiopoietin-2 (ANGPT2) causes compromised vascular integrity in the tumor periphery, leading to impaired T-cell infiltration to the tumor core. The spatial regulation of ANGPT2 in whole tumor cross-sections was analyzed in conjunction with T-cell distribution, vascular integrity, and response to immunotherapy in syngeneic murine melanoma models. T-cell exclusion was associated with ANGPT2 upregulation and elevated vascular leakage at the periphery of human and murine melanomas. Both pharmacologic and genetic blockade of ANGPT2 promoted CD8+ T-cell infiltration into the tumor core, exerting antitumor effects. Importantly, the reversal of T-cell exclusion following ANGPT2 blockade not only enhanced response to anti-PD-1 immune checkpoint blockade therapy in immunogenic, therapy-responsive mouse melanomas, but it also rendered nonresponsive tumors susceptible to immunotherapy. Therapeutic response after ANGPT2 blockade, driven by improved CD8+ T-cell infiltration to the tumor core, coincided with spatial TIE2 signaling activation and increased vascular integrity at the tumor periphery where endothelial expression of adhesion molecules was reduced. These data highlight ANGPT2/TIE2 signaling as a key mediator of T-cell exclusion and a promising target to potentiate immune checkpoint blockade efficacy in melanoma.
SIGNIFICANCE
ANGPT2 limits the efficacy of immunotherapy by inducing vascular destabilization at the tumor periphery to promote T-cell exclusion.
Topics: Humans; Mice; Animals; Angiopoietin-2; Immune Checkpoint Inhibitors; Melanoma; Immunotherapy; CD8-Positive T-Lymphocytes; Tumor Microenvironment
PubMed: 37093870
DOI: 10.1158/0008-5472.CAN-22-2838 -
Heliyon Apr 2024Non-alcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver disease, with a range of conditions including non-alcoholic fatty liver,... (Review)
Review
Non-alcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver disease, with a range of conditions including non-alcoholic fatty liver, non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Currently recognized as the liver component of the metabolic syndrome, NAFLD is intimately linked to metabolic diseases. Angiopoietin-like proteins (ANGPTLs) comprise a class of proteins that resemble angiopoietins structurally. It is closely related to obesity, insulin resistance and lipid metabolism, and may be the critical factor of metabolic syndrome. In recent years, many studies have found that there is a certain correlation between ANGPTLs and the occurrence and progression of NAFLD disease spectrum. This article reviews the possible mechanisms and roles of ANGPTL protein in the pathogenesis and progression of NAFLD.
PubMed: 38560164
DOI: 10.1016/j.heliyon.2024.e27739