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Journal of UOEH 2019Angiopoietins play important roles in angiogenesis and the maintenance of hematopoietic stem cells. Angiopoietin-like proteins (ANGPTLs) are identified as proteins... (Review)
Review
Angiopoietins play important roles in angiogenesis and the maintenance of hematopoietic stem cells. Angiopoietin-like proteins (ANGPTLs) are identified as proteins structurally similar to angiopoietins, and the ANGPTL family now consists of eight members. ANGPTLs are secretary proteins, and some ANGPTLs are not only angiogenic factors but also proteins with multiple functions such as glucose metabolism, lipid metabolism, redox regulation and chronic inflammation. Chronic inflammation is one of the key factors in carcinogenesis and cancer growth, proliferation, invasion and metastasis. ANGPTL 2, 3, 4, 6 and 7 are pro-inflammatory factors and regulate cancer progression, while ANGPTL1 inhibits tumor angiogenesis and metastasis. In this review, we describe the roles of ANGPTLs in cancer progression and discuss the possibility of disturbing the progression of cancer by regulating ANGPTLs expression.
Topics: Angiopoietin-like Proteins; Angiopoietins; Disease Progression; Glucose; Humans; Inflammation; Inflammation Mediators; Lipid Metabolism; Neoplasms; Neovascularization, Pathologic; Oxidation-Reduction
PubMed: 31548486
DOI: 10.7888/juoeh.41.317 -
The Canadian Journal of Cardiology Dec 2023Despite the best pharmacologic tools available, cardiovascular diseases (CVDs) remain a major cause of morbidity and mortality in developed countries. After 2 decades of... (Review)
Review
Despite the best pharmacologic tools available, cardiovascular diseases (CVDs) remain a major cause of morbidity and mortality in developed countries. After 2 decades of research, new therapeutic targets, such as angiopoietin-like proteins (ANGPTLs), are emerging. ANGPTLs belong to a family of 8 members, from ANGPTL1 to ANGPTL8; they have structural homology with angiopoietins and are secreted in the circulation. ANGPTLs display a multitude of physiological and pathologic functions; they contribute to inflammation, angiogenesis, cell death, senescence, hematopoiesis, and play a role in repair, maintenance, and tissue homeostasis. ANGPTLs-particularly the triad ANGPTL3, 4, and 8-have an established role in lipid metabolism through the regulation of triacylglycerol trafficking according to the nutritional status. Some ANGPTLs also contribute to glucose metabolism. Therefore, dysregulation in ANGPTL expression associated with abnormal circulating levels are linked to a plethora of CVD and metabolic disorders including atherosclerosis, heart diseases, diabetes, but also obesity and cancers. Because ANGPTLs bind to different receptors according to the cell type, antagonists are therapeutically inadequate. Recently, direct inhibitors of ANGPTLs, mainly ANGPTL3, have been developed, and specific monoclonal antibodies and antisense oligonucleotides are currently being tested in clinical trials. The aim of the current review is to provide an up-to-date preclinical and clinical overview on the function of the 8 members of the ANGPTL family in the cardiovascular system, their contribution to CVD, and the therapeutic potential of manipulating some of them.
Topics: Humans; Angiopoietin-like Proteins; Cardiovascular Diseases; Obesity; Cardiovascular System; Biology; Angiopoietins; Angiopoietin-Like Protein 3; Angiopoietin-Like Protein 8; Peptide Hormones
PubMed: 37295611
DOI: 10.1016/j.cjca.2023.06.002 -
Cell Oct 2017Angiopoietins signal through TIE receptors to control both developmental and homeostatic processes that can go awry in genetic diseases and cancer. This SnapShot...
Angiopoietins signal through TIE receptors to control both developmental and homeostatic processes that can go awry in genetic diseases and cancer. This SnapShot illustrates key elements of angiopoietin signaling in normal and disease contexts.
Topics: Angiopoietins; Endothelial Cells; Humans; Inflammation; Lymphangiogenesis; Neovascularization, Pathologic
PubMed: 29053972
DOI: 10.1016/j.cell.2017.10.009 -
International Journal of Molecular... Apr 2019Alternative splicing of pre-mRNA allows the generation of multiple splice isoforms from a given gene, which can have distinct functions. In fact, splice isoforms can... (Review)
Review
Alternative splicing of pre-mRNA allows the generation of multiple splice isoforms from a given gene, which can have distinct functions. In fact, splice isoforms can have opposing functions and there are many instances whereby a splice isoform acts as an inhibitor of canonical isoform function, thereby adding an additional layer of regulation to important processes. Angiogenesis is an important process that is governed by alternative splicing mechanisms. This review focuses on the alternative spliced isoforms of key genes that are involved in the angiogenesis process; and .
Topics: Alternative Splicing; Angiopoietins; Animals; Humans; Neovascularization, Pathologic; Receptors, Vascular Endothelial Growth Factor
PubMed: 31027366
DOI: 10.3390/ijms20092067 -
Journal of the American Society of... Jul 2017Systemic inflammation is a hallmark of commonly encountered diseases ranging from bacterial sepsis to sterile syndromes such as major trauma. Derangements in the host... (Review)
Review
Systemic inflammation is a hallmark of commonly encountered diseases ranging from bacterial sepsis to sterile syndromes such as major trauma. Derangements in the host vasculature contribute to the cardinal manifestations of sepsis in profound ways. Recent studies of control pathways regulating the vascular endothelium have illuminated how this single cell layer toggles between quiescence and activation to affect the development of shock and multiorgan dysfunction. This article focuses on one such control pathway, the Tie2 receptor and its ligands the angiopoietins, to describe a growing body of genetic, biochemical, mechanistic, and human studies that implicate Tie2 as a critical switch. In health, activated Tie2 maintains the endothelium in a quiescent state characterized by dynamic barrier function and antiadhesion against circulating leukocytes. In sepsis and related diseases, expression of the angiopoietins becomes markedly imbalanced and Tie2 signaling is greatly attenuated. These rapid molecular changes potentiate pathophysiologic responses throughout the body, resulting in injurious vascular leakage and organ inflammation. The Tie2 axis, therefore, may be a promising avenue for future translational studies.
Topics: Angiopoietins; Animals; Humans; Inflammation; Receptor, TIE-2; Signal Transduction
PubMed: 28465380
DOI: 10.1681/ASN.2017010069 -
Journal of Diabetes Research 2019Diabetic retinopathy (DR) is the commonest cause of blindness in the working-age population of the developed world. The molecular pathophysiology of DR is complex, and a... (Review)
Review
Diabetic retinopathy (DR) is the commonest cause of blindness in the working-age population of the developed world. The molecular pathophysiology of DR is complex, and a complete spatiotemporal model of the disease is still being elucidated. Recently, a role for angiopoietin (Ang) proteins in the pathophysiology of DR has been proposed by several research groups, and several aspects of Ang signalling are being explored as novel therapeutic strategies. Here, we review the role of the Ang proteins in two important forms of DR, diabetic macular oedema and proliferative diabetic retinopathy. The function of the Ang proteins in regulating blood vessel permeability and neovascularisation is discussed, and we also evaluate recent preclinical and clinical studies highlighting the potential benefits of modulating Ang signalling as a treatment for DR.
Topics: Angiopoietins; Animals; Diabetes Complications; Diabetes Mellitus; Diabetic Retinopathy; Humans; Hypoglycemic Agents; Macular Edema; Signal Transduction
PubMed: 31485452
DOI: 10.1155/2019/5140521 -
The New England Journal of Medicine Jul 2017Loss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with decreased plasma levels of triglycerides, low-density lipoprotein (LDL)... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Loss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with decreased plasma levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. It is not known whether such variants or therapeutic antagonism of ANGPTL3 are associated with a reduced risk of atherosclerotic cardiovascular disease.
METHODS
We sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study. We performed tests of association for loss-of-function variants in ANGPTL3 with lipid levels and with coronary artery disease in 13,102 case patients and 40,430 controls from the DiscovEHR study, with follow-up studies involving 23,317 case patients and 107,166 controls from four population studies. We also tested the effects of a human monoclonal antibody, evinacumab, against Angptl3 in dyslipidemic mice and against ANGPTL3 in healthy human volunteers with elevated levels of triglycerides or LDL cholesterol.
RESULTS
In the DiscovEHR study, participants with heterozygous loss-of-function variants in ANGPTL3 had significantly lower serum levels of triglycerides, HDL cholesterol, and LDL cholesterol than participants without these variants. Loss-of-function variants were found in 0.33% of case patients with coronary artery disease and in 0.45% of controls (adjusted odds ratio, 0.59; 95% confidence interval, 0.41 to 0.85; P=0.004). These results were confirmed in the follow-up studies. In dyslipidemic mice, inhibition of Angptl3 with evinacumab resulted in a greater decrease in atherosclerotic lesion area and necrotic content than a control antibody. In humans, evinacumab caused a dose-dependent placebo-adjusted reduction in fasting triglyceride levels of up to 76% and LDL cholesterol levels of up to 23%.
CONCLUSIONS
Genetic and therapeutic antagonism of ANGPTL3 in humans and of Angptl3 in mice was associated with decreased levels of all three major lipid fractions and decreased odds of atherosclerotic cardiovascular disease. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT01749878 .).
Topics: Aged; Angiopoietin-Like Protein 3; Angiopoietin-like Proteins; Angiopoietins; Animals; Antibodies, Monoclonal; Atherosclerosis; Cardiovascular Diseases; Coronary Artery Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Double-Blind Method; Dyslipidemias; Female; Humans; Lipid Metabolism; Lipids; Male; Mice; Mice, Inbred Strains; Middle Aged; Mutation
PubMed: 28538136
DOI: 10.1056/NEJMoa1612790 -
Pulmonology 2023Novel Coronavirus Disease 2019 (Covid-19) is associated with multi-systemic derangement, including circulatory dysfunction with features of endothelial dysfunction,... (Review)
Review
Novel Coronavirus Disease 2019 (Covid-19) is associated with multi-systemic derangement, including circulatory dysfunction with features of endothelial dysfunction, microangiopathic thrombosis and angiocentric inflammation. Recently, intussusceptive angiogenesis has been implicated in the pathogenesis of the disease. Herein, we conducted a narrative review according to the SANRA guidelines to review and discuss data regarding splitting angiogenesis including mechanisms, drivers, regulators and putative roles. Relevant angiogenic features in Covid-19, including their potential role in inflammation, endothelial dysfunction and permeability, as well as their use as prognostic markers and therapeutic roles are reviewed. Splitting angiogenesis in Covid-19 involve hypoxia, hypoxia-inducible factors, classic angiogenic mediators, such as the Vascular Endothelial Growth Factor (VEGF), Angiopoietins, hyperinflammation and cytokine storm, and dysregulation of the Renin-Angiotensin-Aldosterone System, which combined, interact to promote intussusception. Data regarding the use of angiogenic mediators as prognostic tools is summarized and suggest that angiopoietins and VEGF are elevated in Covid-19 patients and predictors of adverse outcomes. Finally, we reviewed the scarce data regarding angiogenic mediators as therapeutic targets. These preliminary findings suggest a potential benefit of bevacizumab as an add-on therapy.
Topics: Humans; SARS-CoV-2; COVID-19; Vascular Endothelial Growth Factor A; Inflammation; Angiopoietins; Hypoxia
PubMed: 34593362
DOI: 10.1016/j.pulmoe.2021.08.004 -
FEBS Letters Oct 2019Angiopoietins (Angs) are a family of vascular growth factors that share multiple cellular functions related to cell survival, proliferation, and migration. Angs play... (Review)
Review
Angiopoietins (Angs) are a family of vascular growth factors that share multiple cellular functions related to cell survival, proliferation, and migration. Angs play physiological and pathological roles through the Tie tyrosine kinase receptors. The Ang-Tie signaling pathway participates in the developmental and tumor-induced angiogenesis and is also involved in many disease settings, such as vascular diseases, systemic inflammation, and cancers. Since Angs are widely expressed in the kidney, an enormous amount of research focuses on their roles in the kidney. In this review, we describe the biological functions of the Ang-Tie signaling pathway and summarize their roles in kidney development and maturation, acute and chronic kidney diseases, diabetic nephropathy, lupus nephropathy, hemolytic uremic syndrome, end-stage renal diseases, and renal cell carcinoma. Understanding the molecular mechanisms of Ang-Tie signaling may reveal potential therapeutic targets for preventing or alleviating kidney diseases.
Topics: Angiopoietins; Animals; Humans; Kidney Diseases; Receptors, TIE; Signal Transduction
PubMed: 31380564
DOI: 10.1002/1873-3468.13568 -
Journal of Cardiac Failure Jul 2021Angiopoietin-1 and 2 (Ang1, Ang2) are important mediators of angiogenesis. Angiopoietin levels are perturbed in cardiovascular disease, but it is unclear whether...
BACKGROUND
Angiopoietin-1 and 2 (Ang1, Ang2) are important mediators of angiogenesis. Angiopoietin levels are perturbed in cardiovascular disease, but it is unclear whether angiopoietin signaling is causative, an adaptive response, or merely epiphenomenon of disease activity.
METHODS AND RESULTS
In a cohort free of cardiovascular disease at baseline (Multi-Ethnic Study of Atherosclerosis [MESA]), relationships between angiopoietins, cardiac morphology, and subsequent incidence of heart failure or cardiovascular death were evaluated. In cohorts with pulmonary arterial hypertension or left heart disease, associations between angiopoietins, invasive hemodynamics, and adverse clinical outcomes were evaluated. In MESA, Ang2 was associated with a higher incidence of heart failure or cardiovascular death (hazard ratio 1.21 per standard deviation, P < .001). Ang2 was associated with increased right atrial pressure (pulmonary arterial hypertension cohort) and increased wedge pressure and right atrial pressure (left heart disease cohort). Elevated Ang2 was associated with mortality in the pulmonary arterial hypertension cohort.
CONCLUSIONS
Ang2 was associated with incident heart failure or death among adults without cardiovascular disease at baseline and with disease severity in individuals with existing heart failure. Our finding that Ang2 is increased before disease onset and that elevations reflect disease severity, suggests Ang2 may contribute to heart failure pathogenesis.
Topics: Adult; Angiopoietin-1; Angiopoietin-2; Angiopoietins; Cardiovascular Diseases; Heart Failure; Humans; Incidence; Severity of Illness Index
PubMed: 33872759
DOI: 10.1016/j.cardfail.2021.04.001