-
Atherosclerosis Jan 2018
Topics: Angiopoietins; Cholesterol, LDL; Lipids; Plasma
PubMed: 29111225
DOI: 10.1016/j.atherosclerosis.2017.10.002 -
Human Molecular Genetics Jul 2023Rare missense and nonsense variants in the Angiopoietin-like 7 (ANGPTL7) gene confer protection from primary open-angle glaucoma (POAG), though the functional mechanism...
Rare missense and nonsense variants in the Angiopoietin-like 7 (ANGPTL7) gene confer protection from primary open-angle glaucoma (POAG), though the functional mechanism remains uncharacterized. Interestingly, a larger variant effect size strongly correlates with in silico predictions of increased protein instability (r = -0.98), suggesting that protective variants lower ANGPTL7 protein levels. Here, we show that missense and nonsense variants cause aggregation of mutant ANGPTL7 protein in the endoplasmic reticulum (ER) and decreased levels of secreted protein in human trabecular meshwork (TM) cells; a lower secreted:intracellular protein ratio strongly correlates with variant effects on intraocular pressure (r = 0.81). Importantly, accumulation of mutant protein in the ER does not increase expression of ER stress proteins in TM cells (P > 0.05 for all variants tested). Cyclic mechanical stress, a glaucoma-relevant physiologic stressor, also significantly lowers ANGPTL7 expression in primary cultures of human Schlemm's canal (SC) cells (-2.4-fold-change, P = 0.01). Collectively, these data suggest that the protective effects of ANGPTL7 variants in POAG stem from lower levels of secreted protein, which may modulate responses to physiologic and pathologic ocular cell stressors. Downregulation of ANGPTL7 expression may therefore serve as a viable preventative and therapeutic strategy for this common, blinding disease.
Topics: Humans; Glaucoma, Open-Angle; Glaucoma; Trabecular Meshwork; Intraocular Pressure; Angiopoietins; Angiopoietin-like Proteins; Angiopoietin-Like Protein 7
PubMed: 37220876
DOI: 10.1093/hmg/ddad083 -
Cold Spring Harbor Perspectives in... Mar 2014The Eph and Tie cell surface receptors mediate a variety of signaling events during development and in the adult organism. As other receptor tyrosine kinases, they are... (Review)
Review
The Eph and Tie cell surface receptors mediate a variety of signaling events during development and in the adult organism. As other receptor tyrosine kinases, they are activated on binding of extracellular ligands and their catalytic activity is tightly regulated on multiple levels. The Eph and Tie receptors display some unique characteristics, including the requirement of ligand-induced receptor clustering for efficient signaling. Interestingly, both Ephs and Ties can mediate different, even opposite, biological effects depending on the specific ligand eliciting the response and on the cellular context. Here we discuss the structural features of these receptors, their interactions with various ligands, as well as functional implications for downstream signaling initiation. The Eph/ephrin structures are already well reviewed and we only provide a brief overview on the initial binding events. We go into more detail discussing the Tie-angiopoietin structures and recognition.
Topics: Angiopoietins; Binding Sites; Enzyme Activation; Ligands; Models, Molecular; Protein Structure, Tertiary; Receptor, TIE-2; Receptors, Eph Family; Signal Transduction
PubMed: 24478383
DOI: 10.1101/cshperspect.a009142 -
The American Journal of Pathology Aug 2022Alveolar capillary dysplasia (ACD) is a rare lung developmental disorder leading to persistent pulmonary arterial hypertension and fatal outcomes in newborns. The...
Alveolar capillary dysplasia (ACD) is a rare lung developmental disorder leading to persistent pulmonary arterial hypertension and fatal outcomes in newborns. The current study analyzed the microvascular morphology and the underlying molecular background of ACD. One ACD group (n = 7), one pulmonary arterial hypertension group (n = 20), and one healthy con1trol group (n = 16) were generated. Samples of histologically confirmed ACD were examined by exome sequencing and array-based comparative genomic hybridization. Vascular morphology was analyzed using scanning electron microscopy of microvascular corrosion casts. Gene expression and biological pathways were analyzed using two panels on inflammation/kinase-specific genes and a comparison analysis tool. Compartment-specific protein expression was analyzed using immunostaining. In ACD, there was an altered capillary network, a high prevalence of intussusceptive angiogenesis, and increased activity of C-X-C motif chemokine receptor 4 (CXCR4), hypoxia-inducible factor 1α (HIF1A), and angiopoietin signaling pathways compared with pulmonary arterial hypertension/healthy controls. Histologically, there was a markedly increased prevalence of endothelial tyrosine kinase receptor (TEK/TIE2) macrophages in ACD, compared with the other groups, whereas the CXCR4 ligand CXCL12 and HIF1A showed high expression in all groups. ACD is characterized by dysfunctional capillaries and a high prevalence of intussusceptive angiogenesis. The results indicate that endothelial CXCR4, HIF1A, and angiopoietin signaling as well as TIE2 macrophages are crucial for the induction of intussusceptive angiogenesis and vascular remodeling. Future studies should address the use of anti-angiogenic agents in ACD, where TIE2 appears as a promising target.
Topics: Angiopoietins; Comparative Genomic Hybridization; Humans; Infant, Newborn; Persistent Fetal Circulation Syndrome; Pulmonary Alveoli; Pulmonary Arterial Hypertension
PubMed: 35649494
DOI: 10.1016/j.ajpath.2022.05.004 -
Actas Dermo-sifiliograficas 2017Angiogenesis is the growth of new blood vessels from pre-existing vessels. It is a biological process essential in physiological wound healing or pathological... (Review)
Review
Angiogenesis is the growth of new blood vessels from pre-existing vessels. It is a biological process essential in physiological wound healing or pathological inflammation and tumor growth, which underlies a complex interplay of stimulating and inhibiting signals. Extracellular matrix, cells of innate and adaptive immunity and endothelial cells itself are a major source of angiogenic factors that activate or inhibit specific receptors and consequently influence intracellular signaling pathways. Most inflammatory and neoplastic diseases in dermatology are characterized by excessive angiogenesis, such as psoriasis, atopic dermatitis, as well as melanoma, non-melanoma skin cancer, but also benign vascular neoplasia. In this article we describe current knowledge of angiogenesis and its most relevant mechanisms in different dermatological disorders with particular emphasis on the angiogenic factors (vascular endothelial growth factor) and angiopoietins as a target of current and future directions of anti-angiogenic therapy.
Topics: Angiogenesis Inhibitors; Angiogenic Proteins; Angiopoietins; Drug Resistance, Neoplasm; Hemangioma; Humans; Melanoma; Molecular Targeted Therapy; Neoplasm Proteins; Neovascularization, Pathologic; Neovascularization, Physiologic; Psoriasis; Receptor, TIE-2; Skin; Skin Diseases; Skin Neoplasms
PubMed: 28162227
DOI: 10.1016/j.ad.2016.12.001 -
Best Practice & Research. Clinical... May 2023ANGPTL3 has emerged as a therapeutic target whose inhibition results in profound reductions of plasma lipids, including atherogenic triglyceride-rich lipoproteins and... (Review)
Review
ANGPTL3 has emerged as a therapeutic target whose inhibition results in profound reductions of plasma lipids, including atherogenic triglyceride-rich lipoproteins and low-density lipoprotein cholesterol. The identification of ANGPTL3 deficiency as a cause of familial combined hypolipidemia in humans hastened the development of anti-ANGPTL3 therapeutic agents, including evinacumab (a monoclonal antibody inhibiting circulating ANGPTL3), vupanorsen (an antisense oligonucleotide [ASO] targeting hepatic ANGPTL3 mRNA for degradation), and others. Advances have also been made in ANGPTL3 vaccination and gene editing strategies, with the former still in preclinical phases and the latter in preparation for Phase 1 trials. Here, we review the discovery of ANGPTL3 as an important regulator of lipoprotein metabolism, molecular characteristics of the protein, mechanisms by which it regulates plasma lipids, and the clinical development of anti-ANGPTL3 agents. The clinical success of therapies inhibiting ANGPTL3 highlights the importance of this target as a novel approach in treating refractory hypertriglyceridemia and hypercholesterolemia.
Topics: Humans; Angiopoietin-like Proteins; Angiopoietin-Like Protein 3; Lipoproteins; Triglycerides; Angiopoietins
PubMed: 35999139
DOI: 10.1016/j.beem.2022.101688 -
The FEBS Journal Feb 2011Obesity and related metabolic diseases, such as type 2 diabetes, hypertension and hyperlipidemia are an increasingly prevalent medical and social problem in developed... (Review)
Review
Obesity and related metabolic diseases, such as type 2 diabetes, hypertension and hyperlipidemia are an increasingly prevalent medical and social problem in developed and developing countries. These conditions are associated with increased risk of cardiovascular disease, the leading cause of death. Therefore, it is important to understand the molecular basis underlying obesity and related metabolic diseases in order to develop effective preventive and therapeutic approaches against these conditions. Recently, a family of proteins structurally similar to the angiogenic-regulating factors known as angiopoietins was identified and designated 'angiopoietin-like proteins' (ANGPTLs). Encoded by seven genes, ANGPTL1-7 all possess an N-terminal coiled-coil domain and a C-terminal fibrinogen-like domain, both characteristic of angiopoietins. ANGPTLs do not bind to either the angiopoietin receptor Tie2 or the related protein Tie1, indicating that these ligands function differently from angiopoietins. Like angiopoietins, some ANGPTLs potently regulate angiogenesis, but ANGPTL3, -4 and ANGPTL6/angiopoietin-related growth factor (AGF) directly regulate lipid, glucose and energy metabolism independent of angiogenic effects. Recently, we found that ANGPTL2 is a key adipocyte-derived inflammatory mediator that links obesity to systemic insulin resistance. In this minireview, we focus on the roles of ANGPTL2 and ANGPTL6/AGF in obesity and related metabolic diseases, and discuss the possibility that both could function as molecular targets for the prevention and treatment of obesity and metabolic diseases.
Topics: Angiopoietins; Animals; Anti-Obesity Agents; Humans; Insulin Resistance; Metabolic Syndrome; Obesity
PubMed: 21182596
DOI: 10.1111/j.1742-4658.2010.07979.x -
Acta Histochemica Dec 2023Idiopathic pulmonary fibrosis (IPF) is considered as a chronic interstitial lung disease with underlying mechanism of IPF remaining unclear, while there are no...
OBJECTIVE
Idiopathic pulmonary fibrosis (IPF) is considered as a chronic interstitial lung disease with underlying mechanism of IPF remaining unclear, while there are no definitive treatment options. In recent years, scientists have gradually paid attention to the influence of angiogenesis on IPF. Because IPF is a progressive with microvascular remodeling disorder, scientists have postulated that angiogenesis may also be one of the initiating and contributing factors of the disease. Bupleurum is a common natural Chinese herbal medicine with antibacterial, anti-inflammatory, anti-tumor and other pharmacological effects. As the most important active monomer of Bupleurum, Saikosaponin-d (SSd) is a new discovery with anti-pulmonary fibrosis (PF) activity. This study attempts to investigate the role of SSd in the interference of PF through regulation of angiogenesis in IPF through Angiopoietin (Angpt) /Tie receptor 2 (Tie2) pathway.
METHODS
Randomly, we allocated C57BL/6 mice into four groups (n = 20 in each group). Afterwards, establishment of IPF model was accomplished via intratracheal administration of bleomycin (BLM, 5 mg/kg), while corresponding drug intervention was given accordingly. On 3rd, 7th, 14th and 28th days after modeling, we performed histopathological examination through staining. Meanwhile, immunohistochemistry (IHC) of PF and the expression of related factors were observed, while Ang/Tie2 pathway was assessed by ELISA with the effect of SSd on angiogenesis related proteins in IPF being explored with IHC and Western Blot technique.
RESULTS
Our results showed that SSd could reduce inflammation and PF levels in lung tissue of experimental mice, while levels of angiogenesis-related factors, namely Tie-2, Ang-1 and ANGPT2 (Ang-2), fibrosis- associated factors like Alpha-smooth muscle actin (α-SMA), collagen-I and hydroxyproline in SSd and dexamethasone (DXM) mice were significantly reduced at each time point compared to BLM (p < 0.01). Additionally, we discovered substantial decreased expressions of Ang-1, Ang-2, Tie-2, α-SMA and collagen-I at protein level in SSd and DXM mice at each time point compared to BLM (p < 0.05). Besides, insignificant differences were observed between SSd and DXM groups (p > 0.05).
CONCLUSION
This study has demonstrated that SSd could down-regulate the expression of ANG-1, Ang-2 and Tie2 in the Ang/Tie2 pathway, and may reduce lung inflammation and PF in BLM-induced mice via inhibition of angiogenesis.
Topics: Mice; Animals; Angiopoietins; Mice, Inbred C57BL; Lung; Idiopathic Pulmonary Fibrosis; Collagen Type I; Bleomycin
PubMed: 37837833
DOI: 10.1016/j.acthis.2023.152100 -
Proceedings of the National Academy of... Mar 2023Necrosis in the tumor interior is a common feature of aggressive cancers that is associated with poor clinical prognosis and the development of metastasis. How the...
Necrosis in the tumor interior is a common feature of aggressive cancers that is associated with poor clinical prognosis and the development of metastasis. How the necrotic core promotes metastasis remains unclear. Here, we report that emergence of necrosis inside the tumor is correlated temporally with increased tumor dissemination in a rat breast cancer model and in human breast cancer patients. By performing spatially focused transcriptional profiling, we identified angiopoietin-like 7 (Angptl7) as a tumor-specific factor localized to the perinecrotic zone. Functional studies showed that Angptl7 loss normalizes central necrosis, perinecrotic dilated vessels, metastasis, and reduces circulating tumor cell counts to nearly zero. Mechanistically, Angptl7 promotes vascular permeability and supports vascular remodeling in the perinecrotic zone. Taken together, these findings show that breast tumors actively produce factors controlling central necrosis formation and metastatic dissemination from the tumor core.
Topics: Animals; Female; Humans; Rats; Angiopoietin-Like Protein 7; Angiopoietin-like Proteins; Angiopoietins; Breast Neoplasms; Mammary Neoplasms, Animal; Necrosis; Neoplastic Cells, Circulating
PubMed: 36853945
DOI: 10.1073/pnas.2214888120 -
Mediators of Inflammation 2015The development of the syndrome of cancer cachexia and that of metastasis are related with a poor prognostic for cancer patients. They are considered multifactorial... (Review)
Review
The development of the syndrome of cancer cachexia and that of metastasis are related with a poor prognostic for cancer patients. They are considered multifactorial processes associated with a proinflammatory environment, to which tumour microenvironment and other tissues from the tumour bearing individuals contribute. The aim of the present review is to address the role of ghrelin, myostatin, leptin, HIF, IL-6, TNF-α, and ANGPTL-4 in the regulation of energy balance, tumour development, and tumoural cell invasion. Hypoxia induced factor plays a prominent role in tumour macro- and microenvironment, by modulating the release of proinflammatory cytokines.
Topics: Angiopoietin-Like Protein 4; Angiopoietins; Animals; Cachexia; Cytokines; Ghrelin; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Inflammation; Interleukin-6; Leptin; Myostatin; Neoplasm Metastasis; Neoplasms; Prognosis; Syndrome; Tumor Microenvironment; Tumor Necrosis Factor-alpha
PubMed: 26508818
DOI: 10.1155/2015/791060