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The Journal of Clinical Investigation May 2024Lymphedema is a debilitating disease with no effective cure and affects an estimated 250 million individuals worldwide. Prior studies have identified mutations in...
Lymphedema is a debilitating disease with no effective cure and affects an estimated 250 million individuals worldwide. Prior studies have identified mutations in piezo-type mechanosensitive ion channel component 1 (PIEZO1), angiopoietin 2 (ANGPT2), and tyrosine kinase with Ig-like and EGF-like domains 1 (TIE1) in patients with primary lymphedema. Here, we identified crosstalk between these molecules and showed that activation of the mechanosensory channel PIEZO1 in lymphatic endothelial cells (LECs) caused rapid exocytosis of the TIE ligand ANGPT2, ectodomain shedding of TIE1 by disintegrin and metalloproteinase domain-containing protein 17 (ADAM17), and increased TIE/PI3K/AKT signaling, followed by nuclear export of the transcription factor FOXO1. These data establish a functional network between lymphedema-associated genes and provide what we believe to be the first molecular mechanism bridging channel function with vascular signaling and intracellular events culminating in transcriptional regulation of genes expressed in LECs. Our study provides insights into the regulation of lymphatic function and molecular pathways involved in human disease.
Topics: Animals; Humans; Mice; ADAM17 Protein; Angiopoietin-2; Endothelial Cells; Forkhead Box Protein O1; Ion Channels; Lymphangiogenesis; Lymphedema; Mechanotransduction, Cellular; Receptor, TIE-1; Signal Transduction
PubMed: 38747287
DOI: 10.1172/JCI176577 -
Alternative Therapies in Health and... May 2024This study aimed to investigate the changes in angiopoietin-2 and tumor necrosis factor α levels in patients with acute myocardial infarction complicated with pulmonary...
OBJECTIVE
This study aimed to investigate the changes in angiopoietin-2 and tumor necrosis factor α levels in patients with acute myocardial infarction complicated with pulmonary infection.
METHODS
Retrospective selection was conducted on 61 patients with acute myocardial infarction complicated with pulmonary infection and 122 patients with simple acute myocardial infarction. A comparison was made between the two groups regarding general information and serum myocs. The distribution and drug resistance of pathogenic bacteria were also explored.
RESULTS
The study showed significant differences in the duration of alcohol consumption, the proportion of diabetes mellitus, and levels of certain markers (serum cardiac troponin T, creatine kinase isoenzyme, myoglobin, angiopoietin-2, tumor necrosis factor α) between the two groups (P < .05). Logistic regression analysis identified elevated levels of serum angiopoietin-2 and tumor necrosis factor α, along with diabetes mellitus, as independent risk factors for acute myocardial infarction complicated with pulmonary infection (P < .05). Pearson correlation analysis demonstrated a positive correlation between serum angiopoietin-2 and tumor necrosis factor α levels and CPI scores in patients (P < .05). ROC curve analysis indicated that combined diagnosis of serum angiopoietin-2 and tumor necrosis factor α had an AUC of 0.867, with a sensitivity of 85.25% and specificity of 77.87% for detecting acute myocardial infarction complicated with pulmonary infection. Among the sputum culture specimens, gram-negative bacteria accounted for 55.34%, gram-positive bacteria for 39.81%, and fungi for 4.85%. Gram-negative bacteria like Klebsiella pneumoniae and Escherichia coli showed high resistance to various antibiotics, while gram-positive bacteria like Streptococcus pneumoniae and Staphylococcus aureus had relatively low resistance to specific antibiotics.
CONCLUSION
Gram-negative bacteria were the main pathogens and exhibited resistance to several antibiotics. Increased levels of angiopoietin-2 and tumor necrosis factor α were observed. Early detection of these markers can assist in the clinical diagnosis and guide the appropriate use of antibiotics.
PubMed: 38743883
DOI: No ID Found -
Journal of Advanced Research May 2024The N-terminal domain of angiopoietin-like protein 3 (ANGPTL3) inhibits lipoprotein lipase activity. Its C-terminal fibrinogen-like (FBN) domain is a ligand of...
INTRODUCTION
The N-terminal domain of angiopoietin-like protein 3 (ANGPTL3) inhibits lipoprotein lipase activity. Its C-terminal fibrinogen-like (FBN) domain is a ligand of macrophage integrin αvβ3.
OBJECTIVES
ANGPTL3 might home to plaque where it directly regulates macrophage function via integrin αvβ3 for atherosclerosis progression.
METHODS
Ldlr mice on a high-fat diet and ApoE mice on a chow diet were received adeno-associated virus (AAV)-mediated Angptl3 gene transfer and followed up for 12 weeks. ApoE mice were injected AAV containing FLAG-tagged Angptl3 cDNA for tracing. Atherosclerotic features were compared between Angptl3ApoE mice and ApoE littermates. THP-1 cells were exposed to 0 or 50 μg/ml ANGPTL3 FBN domain for 24 h to evaluate Toll-like receptor (TLR)4 expression using western blot analysis and circulating cytokine and chemokine profiles by the MILLIPLEX MAP assay. Phospho-proteomic profile was established in ANGPTL3-treated macrophages. Integrin β3 deficient THP-1 cells were obtained by sgRNAs targeting RGD sequence using Lentivirus-Cas9 system.
RESULTS
Angptl3 overexpression increased atherosclerotic progression and CD68 macrophages in plaque (p < 0.05 for all). By immunostaining, FLAG cells were identified in plaque of gene transferred ApoE mice. Fluorescent immunostaining detected co-localisation of Angptl3 and CD68 in plaque macrophages. Phospho-proteomic analysis revealed that Angptl3 induced phosphorylation of proteins that were involved in the IL-17 signalling pathway in THP-1 cells. In vitro, ANGPTL3 treatment increased the production of interleukin (IL)-1β and tumour necrosis factor-α in THP-1 cells (p < 0.05 for both). Exposure of ANGPTL3 to THP-1 cells induced Akt phosphorylation which was weakened in integrin β3 deficient ones. ANGPTL3 elevated TLR4 expression via Akt phosphorylation. In response to lipopolysaccharide, nuclear factor-κB activity was 2.2-fold higher in THP-1 cells pre-treated with ANGPTL3 than in untreated cells (p < 0.05).
CONCLUSIONS
Targeting ANGPTL3 could yield a dual benefit of lowering lipid levels in the blood and suppressing macrophage activation in plaque.
PubMed: 38740260
DOI: 10.1016/j.jare.2024.05.011 -
Diagnostics (Basel, Switzerland) Apr 2024To assess changes in choriocapillaris (CC) vascular density surrounding macular neovascularization (MNV) in age-related macular degeneration (AMD) when transitioning...
To assess changes in choriocapillaris (CC) vascular density surrounding macular neovascularization (MNV) in age-related macular degeneration (AMD) when transitioning from various anti-VEGF treatments to faricimab, using optical coherence tomography angiography (OCTA). 25 eyes of 22 individuals who underwent intravitreal faricimab injections for neovascular AMD with type 1 MNV were included. OCTA images were obtained prior to (T0), after one (T1), and after three faricimab injections (T2); Noteworthy changes occurred in the first ring at T2 in comparison to T0. The percentage of CC flow deficit (FD%), FD average area (FDa), and FD number (FDn) in 5 rings (R1-R5) surrounding the dark halo around the MNV were calculated. A reduction in FD% at T2 compared to T0 (50.5 ± 10.2% at T0, 46.4 ± 10.6% at T2; = 0.020) was seen, indicating CC reperfusion. Additionally, we observed a reduction in the average FDa (140.2 ± 172.1% at T0, 93.7 ± 101.8% at T2; = 0.029). Our study highlights an FD% after three consecutive faricimab injections. The most pronounced effect was observed in the first ring, directly adjacent to the dark halo, suggesting a partial CC reperfusion surrounding the MNV, potentially indicating disease regression.
PubMed: 38732315
DOI: 10.3390/diagnostics14090901 -
Microvascular Research Jul 2024Critical illness is associated with organ failure, in which endothelial hyperpermeability and tissue edema play a major role. The endothelial angiopoietin/Tie2 system, a...
INTRODUCTION
Critical illness is associated with organ failure, in which endothelial hyperpermeability and tissue edema play a major role. The endothelial angiopoietin/Tie2 system, a regulator of endothelial permeability, is dysbalanced during critical illness. Elevated circulating angiopoietin-2 and decreased Tie2 receptor levels are reported, but it remains unclear whether they cause edema independent of other critical illness-associated alterations. Therefore, we have studied the effect of angiopoietin-2 administration and/or reduced Tie2 expression on microvascular leakage and edema under normal conditions.
METHODS
Transgenic male mice with partial deletion of Tie2 (heterozygous exon 9 deletion, Tie2) and wild-type controls (Tie2) received 24 or 72 pg/g angiopoietin-2 or PBS as control (n = 12 per group) intravenously. Microvascular leakage and edema were determined by Evans blue dye (EBD) extravasation and wet-to-dry weight ratio, respectively, in lungs and kidneys. Expression of molecules related to endothelial angiopoietin/Tie2 signaling were determined by ELISA and RT-qPCR.
RESULTS
In Tie2 mice, angiopoietin-2 administration increased EBD extravasation (154 %, p < 0.05) and wet-to-dry weight ratio (133 %, p < 0.01) in lungs, but not in the kidney compared to PBS. Tie2 mice had higher pulmonary (143 %, p < 0.001), but not renal EBD extravasation, compared to wild-type control mice, whereas a more pronounced wet-to-dry weight ratio was observed in lungs (155 %, p < 0.0001), in contrast to a minor higher wet-to-dry weight ratio in kidneys (106 %, p < 0.05). Angiopoietin-2 administration to Tie2 mice did not further increase pulmonary EBD extravasation, pulmonary wet-to-dry weight ratio, or renal wet-to-dry weight ratio. Interestingly, angiopoietin-2 administration resulted in an increased renal EBD extravasation in Tie2 mice compared to Tie2 mice receiving PBS. Both angiopoietin-2 administration and partial deletion of Tie2 did not affect circulating angiopoietin-1, soluble Tie2, VEGF and NGAL as well as gene expression of angiopoietin-1, -2, Tie1, VE-PTP, ELF-1, Ets-1, KLF2, GATA3, MMP14, Runx1, VE-cadherin, VEGFα and NGAL, except for gene and protein expression of Tie2, which was decreased in Tie2 mice compared to Tie2 mice.
CONCLUSIONS
In mice, the microvasculature of the lungs is more vulnerable to angiopoietin-2 and partial deletion of Tie2 compared to those in the kidneys with respect to microvascular leakage and edema.
Topics: Animals; Receptor, TIE-2; Angiopoietin-2; Male; Capillary Permeability; Lung; Kidney; Signal Transduction; Mice, Knockout; Mice; Mice, Inbred C57BL; Pulmonary Edema; Disease Models, Animal; Edema; Mice, Transgenic; Ribonuclease, Pancreatic
PubMed: 38723844
DOI: 10.1016/j.mvr.2024.104694 -
Scientific Reports May 2024Abnormal angiogenesis leads to tumor progression and metastasis in colorectal cancer (CRC). This study aimed to elucidate the association between angiogenesis-related...
Abnormal angiogenesis leads to tumor progression and metastasis in colorectal cancer (CRC). This study aimed to elucidate the association between angiogenesis-related genes, including VEGF-A, ANGPT-1, and ANGPT-2 with both metastatic and microsatellite alterations at selected tetranucleotide repeats (EMAST) subtypes of CRC. We conducted a thorough assessment of the ANGPT-1, ANGPT-2, and VEGF-A gene expression utilizing publicly available RNA sequencing and microarray datasets. Then, the experimental validation was performed in 122 CRC patients, considering their disease metastasis and EMAST profile by using reverse transcription polymerase chain reaction (RT-PCR). Subsequently, a competing endogenous RNA (ceRNA) network associated with these angiogenesis-related genes was constructed and analyzed. The expression level of VEGF-A and ANGPT-2 genes were significantly higher in tumor tissues as compared with normal adjacent tissues (P-value < 0.001). Nevertheless, ANGPT-1 had a significantly lower expression in tumor samples than in normal colon tissue (P-value < 0.01). We identified a significantly increased VEGF-A (P-value = 0.002) and decreased ANGPT-1 (P-value = 0.04) expression in EMAST colorectal tumors. Regarding metastasis, a significantly increased VEGF-A and ANGPT-2 expression (P-value = 0.001) and decreased ANGPT-1 expression (P-value < 0.05) were established in metastatic CRC patients. Remarkably, co-expression analysis also showed a strong correlation between ANGPT-2 and VEGF-A gene expressions. The ceRNA network was constructed by ANGPT-1, ANGPT-2, VEGF-A, and experimentally validated miRNAs (hsa-miR-190a-3p, hsa-miR-374c-5p, hsa-miR-452-5p, and hsa-miR-889-3p), lncRNAs (AFAP1-AS1, KCNQ1OT1 and MALAT1), and TFs (Sp1, E2F1, and STAT3). Network analysis revealed that colorectal cancer is amongst the 82 significant pathways. We demonstrated a significant differential expression of VEGF-A and ANGPT-1 in colorectal cancer patients exhibiting the EMAST phenotype. This finding provides novel insights into the molecular pathogenesis of colorectal cancer, specifically in EMAST subtypes. Yet, the generalization of in silico findings to EMAST colorectal cancer warrants future experimental investigations. In the end, this study proposes that the EMAST biomarker could serve as an additional perspective on CMS4 biology which is well-defined by activated angiogenesis and worse overall survival.
Topics: Humans; Colorectal Neoplasms; Vascular Endothelial Growth Factor A; Neovascularization, Pathologic; Angiopoietin-1; Gene Expression Regulation, Neoplastic; Angiopoietin-2; Male; Female; Middle Aged; Neoplasm Metastasis; Aged; Microsatellite Repeats; Gene Expression Profiling; Gene Regulatory Networks; Angiogenesis
PubMed: 38719941
DOI: 10.1038/s41598-024-61000-x -
Atherosclerosis Jun 2024Carriers of the E40K loss-of-function variant in Angiopoietin-like 4 (ANGPTL4), have lower plasma triglyceride levels as well as lower rates of coronary artery disease...
BACKGROUND
Carriers of the E40K loss-of-function variant in Angiopoietin-like 4 (ANGPTL4), have lower plasma triglyceride levels as well as lower rates of coronary artery disease (CAD) and type 2 diabetes (T2D). These genetic data suggest ANGPTL4 inhibition as a potential therapeutic target for cardiometabolic diseases. However, it is unknown whether the association between E40K and human diseases is due to linkage disequilibrium confounding. The broader impact of genetic ANGPTL4 inhibition is also unknown, raising uncertainties about the safety and validity of this target.
METHODS
To assess the impact of ANGPLT4 inhibition, we evaluated whether E40K and other loss-of-function variants in ANGPTL4 influenced a wide range of health markers and diseases using 29 publicly available genome-wide association meta-analyses of cardiometabolic traits and diseases, as well as 1589 diseases assessed in electronic health records within FinnGen (n = 309,154). To determine whether these relationships were likely causal, and not driven by other correlated variants, we used the Bayesian fine mapping algorithm CoPheScan.
RESULTS
The CoPheScan posterior probability of E40K being the causal variant for triglyceride levels was 99.99 %, validating the E40K to proxy lifelong lower activity of ANGPTL4. The E40K variant was associated with lower risk of CAD (odds ratio [OR] = 0.84, 95 % CI = 0.81 to 0.87, p=3.6e-21) and T2D (OR = 0.91, 95 % CI = 0.87 to 0.95, p=2.8e-05) in GWAS meta-analyses, with results replicated in FinnGen. These significant results were also replicated using other rare loss-of-function variants identified through whole exome sequencing in 488,278 participants of the UK Biobank. Using a Mendelian randomization study design, the E40K variant effect on cardiometabolic diseases was concordant with lipoprotein lipase enhancement (r = 0.82), but not hepatic lipase enhancement (r = -0.10), suggesting that ANGPTL4 effects on cardiometabolic diseases are potentially mainly mediated through lipoprotein lipase. After correction for multiple testing, the E40K variant did not significantly increase the risk of any of the 1589 diseases tested in FinnGen.
CONCLUSIONS
ANGPTL4 inhibition may represent a potentially safe and effective target for cardiometabolic diseases prevention or treatment.
Topics: Humans; Angiopoietin-Like Protein 4; Phenotype; Genome-Wide Association Study; Loss of Function Mutation; Genetic Predisposition to Disease; Diabetes Mellitus, Type 2; Triglycerides; Coronary Artery Disease; Bayes Theorem; Risk Factors; Lipoprotein Lipase
PubMed: 38703417
DOI: 10.1016/j.atherosclerosis.2024.117558 -
Heliyon Apr 2024Familial combined hypolipidemia, previously known as Familial hypobetalipoproteinemia 2 (FHBL2) is considered as an extremely rare recessive disease. Here, we present...
Familial combined hypolipidemia, previously known as Familial hypobetalipoproteinemia 2 (FHBL2) is considered as an extremely rare recessive disease. Here, we present the case of familial combined hypolipidemia with homozygous loss-of function (LOF) variants in angiopoietin-like protein 3 () ((NM_014495.4) c.439_442del (p.Thr146_Asn147insTer)) using panel sequencing (46 yr male whose LDL cholesterol = 34 mg/dL). The serum level of ANGPTL3 was quite low (undetectable). Despite of extreme decreasing LDL cholesterol, this case did not have any complications as hypobetalipidemia (HBL), such as steatorrhea vomiting, hematological, neuromuscular, or ophthalmological symptoms. In addition, we did not find any systemic atherosclerosis in his carotid arteries and in coronary arteries. Based on the findings suggest that inhibition of ANGPTL3 effectively reduce LDL cholesterol without any apparent side effects, although it is still unclear if he will suffer any disadvantages because of this situation in the future.
PubMed: 38699738
DOI: 10.1016/j.heliyon.2024.e29924 -
Computational and Structural... Dec 2024Patients with RA are at a higher risk of developing CV diseases than the general population. The precise mechanisms are still unknown. We evaluated the associations...
Angiopoietin-2, vascular endothelial growth factor family, and heparin binding endothelial growth factor are associated with subclinical atherosclerosis in rheumatoid arthritis.
INTRODUCTION
Patients with RA are at a higher risk of developing CV diseases than the general population. The precise mechanisms are still unknown. We evaluated the associations between 8 plasma growth factors (GFs) (angiopoietin-2, EGF, HB-EGF, PLGF, TGF-α, VEGFa, VEGFc, and VEGFd) and subclinical arteriosclerosis in RA patients.
MATERIALS AND METHODS
A total of 199 patients with RA treated at the Hospital Universitari Sant Joan de Reus (Spain) between 2011 and 2015 were included in this cross-sectional study. Carotid intima media thickness (cIMT), carotid plaque presence (cPP) and pulse wave velocity (PWV) were measured. GFs were measured with Bio-Plex Pro Human Cancer Biomarker Panel 2 (Bio-Rad). Multivariate models and partial least square discriminant analysis (PLS-DA) were used for analysis (RStudio, version 4.0.1).
RESULTS
Multivariate models showed that angiopoietin-2 was associated with cPP and PWV in the overall cohort (OR = 1.53 and β = 0.20, respectively). VEGFc (β = 0.29), VEGFa (β = 0.26) and HB-EGF (β = 0.22) were also associated with PWV. VEGFa (OR = 2.36), VEGFd (OR = 2.29), EGF (OR = 2.62), PLGF (OR = 2.54), and HB-EGF (OR = 2.24) were associated with cPP in men. According to PLS-DA, GFs were able to distinguish between patients with and without cPP in the overall cohort, male cohort, and female cohort. In women, angiopoietin-2 was associated with PWV (β = 0.18).
CONCLUSIONS
The selected GFs were closely related to atherosclerosis in patients with RA and are potential predictors of CV disease in patients with RA.
PubMed: 38689721
DOI: 10.1016/j.csbj.2024.04.042 -
Frontiers in Bioscience (Landmark... Mar 2024The endogenous metabolism of polyunsaturated fatty acids is regulated by the fatty acid desaturase (FADS) gene cluster and is strongly associated with diseases such as...
BACKGROUND
The endogenous metabolism of polyunsaturated fatty acids is regulated by the fatty acid desaturase (FADS) gene cluster and is strongly associated with diseases such as atherosclerosis, dyslipidemia, and type 2 diabetes. However, the association between FADS and atherosclerosis remains a subject of debate.
METHODS
In this study, we specifically investigated the physiological role of Δ-5 fatty acid desaturase (FADS1) in aortic and peripheral vessel (namely, the femoral artery) atherosclerosis by targeting the selective knockdown of hepatic in apolipoprotein E-null (ApoE-/-) mice with antisense oligonucleotides (ASOs).
RESULTS
Knockdown of hepatic in ApoE-/- mice exacerbated aortic atherosclerosis and non-alcoholic fatty liver disease (NAFLD), resulting in weight loss. Upregulation of FADS1 mRNA expression in more severe atherosclerosis vascular tissues potentially caused the upregulation of angiopoietin-like 4 expression.
CONCLUSIONS
Our study demonstrated that knockdown of hepatic in ApoE-/- mice aggravates spontaneous atherosclerosis and NAFLD but does not affect peripheral atherosclerosis (femoral artery) induced by vascular cuff combined with tandem stenosis.
Topics: Animals; Fatty Acid Desaturases; Delta-5 Fatty Acid Desaturase; Atherosclerosis; Liver; Apolipoproteins E; Mice; Gene Knockdown Techniques; Male; Non-alcoholic Fatty Liver Disease; Mice, Inbred C57BL; Mice, Knockout; Oligonucleotides, Antisense
PubMed: 38682200
DOI: 10.31083/j.fbl2904131