Редактирование: ADAM17

Disintegrin and metalloproteinase domain-containing protein 17 precursor (EC 3.4.24.86) (ADAM 17) (Snake venom-like protease) (TNF-alpha convertase) (TNF-alpha-converting enzyme) (CD156b antigen) [CSVP] [TACE]

==Publications==

{{medline-entry
|title=[[ACE2]]/[[ADAM17]]/[[TMPRSS2]] Interplay May Be the Main Risk Factor for COVID-19.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33117379
|abstract=The Coronavirus Disease 2019 (COVID-19) has already caused hundreds of thousands of deaths worldwide in a few months. Cardiovascular disease, hypertension, diabetes and chronic lung disease have been identified as the main COVID-19 comorbidities. Moreover, despite similar infection rates between men and women, the most severe course of the disease is higher in elderly and co-morbid male patients. Therefore, the occurrence of specific comorbidities associated with renin-angiotensin system (RAS) imbalance mediated by the interaction between angiotensin-converting enzyme 2 ([[ACE2]]) and desintegrin and metalloproteinase domain 17 ([[ADAM17]]), along with specific genetic factors mainly associated with type II transmembrane serine protease ([[TMPRSS2]]) expression, could be decisive for the clinical outcome of COVID-19. Indeed, the exacerbated [[ADAM17]]-mediated [[ACE2]], [[TNF]]-α, and IL-6R secretion emerges as a possible underlying mechanism for the acute inflammatory immune response and the activation of the coagulation cascade. Therefore, in this review, we focus on the main pathophysiological aspects of [[ACE2]], [[ADAM17]], and [[TMPRSS2]] host proteins in COVID-19. Additionally, we discuss a possible mechanism to explain the deleterious effect of [[ADAM17]] and [[TMPRSS2]] over-activation in the COVID-19 outcome.
|mesh-terms=* ADAM17 Protein
* Aged
* Aging
* Angiotensin-Converting Enzyme 2
* Betacoronavirus
* COVID-19
* Comorbidity
* Coronavirus Infections
* Female
* Humans
* Male
* Pandemics
* Peptidyl-Dipeptidase A
* Pneumonia, Viral
* Receptors, Interleukin-6
* Risk Factors
* SARS-CoV-2
* Serine Endopeptidases
* Tumor Necrosis Factor-alpha
|keywords=* ACE2
* ADAM17
* COVID-19 pathophysiology
* SARS-CoV-2
* TMPRSS2
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575774
}}
{{medline-entry
|title=DNA methylation analysis on purified neurons and glia dissects age and Alzheimer's disease-specific changes in the human cortex.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30045751
|abstract=Epigenome-wide association studies (EWAS) based on human brain samples allow a deep and direct understanding of epigenetic dysregulation in Alzheimer's disease (AD). However, strong variation of cell-type proportions across brain tissue samples represents a significant source of data noise. Here, we report the first EWAS based on sorted neuronal and non-neuronal (mostly glia) nuclei from postmortem human brain tissues. We show that cell sorting strongly enhances the robust detection of disease-related DNA methylation changes even in a relatively small cohort. We identify numerous genes with cell-type-specific methylation signatures and document differential methylation dynamics associated with aging specifically in neurons such as [[CLU]], [[SYNJ2]] and [[NCOR2]] or in glia [[RAI1]],CXXC5 and [[INPP5A]]. Further, we found neuron or glia-specific associations with AD Braak stage progression at genes such as [[MCF2L]], [[ANK1]], [[MAP2]], [[LRRC8B]], [[STK32C]] and [[S100B]]. A comparison of our study with previous tissue-based EWAS validates multiple AD-associated DNA methylation signals and additionally specifies their origin to neuron, e.g., [[HOXA3]] or glia ([[ANK1]]). In a meta-analysis, we reveal two novel previously unrecognized methylation changes at the key AD risk genes [[APP]] and [[ADAM17]]. Our data highlight the complex interplay between disease, age and cell-type-specific methylation changes in AD risk genes thus offering new perspectives for the validation and interpretation of large EWAS results.
|mesh-terms=* ADAM17 Protein
* Aging
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Autopsy
* Cell Separation
* DNA Methylation
* Epigenesis, Genetic
* Epigenomics
* Genetic Predisposition to Disease
* Genome-Wide Association Study
* Humans
* Neuroglia
* Neurons
* Organ Specificity
* Transcriptome
|keywords=* Aging
* Alzheimer’s disease
* Brain
* Cell sorting
* DNA methylation
* EWAS
* Epigenetics
* Glia
* Neurodegeneration
* Neuron
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058387
}}
{{medline-entry
|title=Role of Adipose Tissue Endothelial [[ADAM17]] in Age-Related Coronary Microvascular Dysfunction.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28473444
|abstract=A disintegrin and metalloproteinase [[ADAM17]] (tumor necrosis factor-α [[[TNF]]]-converting enzyme) regulates soluble [[TNF]] levels. We tested the hypothesis that aging-induced activation in adipose tissue (AT)-expressed [[ADAM17]] contributes to the development of remote coronary microvascular dysfunction in obesity. Coronary arterioles (CAs, ≈90 µm) from right atrial appendages and mediastinal AT were examined in patients (aged: 69±11 years, BMI: 30.2±5.6 kg/m ) who underwent open heart surgery. CA and AT were also studied in 6-month and 24-month lean and obese mice fed a normal or high-fat diet. We found that obesity elicited impaired endothelium-dependent CA dilations only in older patients and in aged high-fat diet mice. Transplantation of AT from aged obese, but not from young or aged, mice increased serum cytokine levels, including [[TNF]], and impaired CA dilation in the young recipient mice. In patients and mice, obesity was accompanied by age-related activation of [[ADAM17]], which was attributed to vascular endothelium-expressed [[ADAM17]]. Excess, [[ADAM17]]-shed [[TNF]] from AT arteries in older obese patients was sufficient to impair CA dilation in a bioassay in which the AT artery was serially connected to a CA. Moreover, we found that the increased activity of endothelial [[ADAM17]] is mediated by a diminished inhibitory interaction with caveolin-1, owing to age-related decline in caveolin-1 expression in obese patients and mice or to genetic deletion of caveolin-1. The present study indicates that aging and obesity cooperatively reduce caveolin-1 expression and increase vascular endothelial [[ADAM17]] activity and soluble [[TNF]] release in AT, which may contribute to the development of remote coronary microvascular dysfunction in older obese patients.
|mesh-terms=* ADAM17 Protein
* Adipose Tissue
* Adult
* Age Factors
* Aged
* Aged, 80 and over
* Aging
* Animals
* Arterioles
* Caveolin 1
* Cells, Cultured
* Coronary Artery Disease
* Coronary Vessels
* Diet, High-Fat
* Disease Models, Animal
* Endothelial Cells
* Female
* Humans
* Male
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* Middle Aged
* Obesity
* RNA Interference
* Risk Factors
* Signal Transduction
* Transfection
* Tumor Necrosis Factor-alpha
* Vasodilation
|keywords=* adipose tissue
* aging
* caveolin 1
* endothelium
* humans
* obesity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484536
}}
{{medline-entry
|title=Selective Inhibition of [[ADAM17]] Efficiently Mediates Glycoprotein Ibα Retention During Ex Vivo Generation of Human Induced Pluripotent Stem Cell-Derived Platelets.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28297575
|abstract=Donor-independent platelet concentrates for transfusion can be produced in vitro from induced pluripotent stem cells (iPSCs). However, culture at 37°C induces ectodomain shedding on platelets of glycoprotein Ibα (GPIbα), the von Willebrand factor receptor critical for adhesive function and platelet lifetime in vivo, through temperature-dependent activation of a disintegrin and metalloproteinase 17 ([[ADAM17]]). The shedding can be suppressed by using inhibitors of panmetalloproteinases and possibly of the upstream regulator p38 mitogen-activated protein kinase (p38 MAPK), but residues of these inhibitors in the final platelet products may be accompanied by harmful risks that prevent clinical application. Here, we optimized the culture conditions for generating human iPSC-derived GPIbα  platelets, focusing on culture temperature and additives, by comparing a new and safe selective [[ADAM17]] inhibitor, KP-457, with previous inhibitors. Because cultivation at 24°C (at which conventional platelet concentrates are stored) markedly diminished the yield of platelets with high expression of platelet receptors, 37°C was requisite for normal platelet production from iPSCs. KP-457 blocked GPIbα shedding from iPSC platelets at a lower half-maximal inhibitory concentration than panmetalloproteinase inhibitor GM-6001, whereas p38 MAPK inhibitors did not. iPSC platelets generated in the presence of KP-457 exhibited improved GPIbα-dependent aggregation not inferior to human fresh platelets. A thrombus formation model using immunodeficient mice after platelet transfusion revealed that iPSC platelets generated with KP-457 exerted better hemostatic function in vivo. Our findings suggest that KP-457, unlike GM-6001 or p38 MAPK inhibitors, effectively enhances the production of functional human iPSC-derived platelets at 37°C, which is an important step toward their clinical application. Stem Cells Translational Medicine 2017;6:720-730.
|mesh-terms=* ADAM17 Protein
* Aging
* Blood Platelets
* Carbonyl Cyanide m-Chlorophenyl Hydrazone
* Cells, Cultured
* Hematopoietic Stem Cells
* Hemostasis
* Humans
* Induced Pluripotent Stem Cells
* Megakaryocytes
* Platelet Glycoprotein GPIb-IX Complex
* Temperature
* Thrombopoiesis
|keywords=* Cell culture
* Cell transplantation
* Induced pluripotent stem cell
* Megakaryocyte
* Mitogen-activated protein kinase
* Thrombopoiesis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442763
}}
{{medline-entry
|title=[The effect of PNS on the content and activity of alpha-secretase in the brains of SAMP8 mice with alzheimer's disease].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23627094
|abstract=To explore the effects of PNS on the content and activity of alpha-secretase in the brains of SAMP8 mice with Alzheimer's disease. SAMP8 mice were randomly divided into four groups: PNS high-dosage group, PNS low-dosage group, huperzine A group and control group. The high-dosage group and low-dosage group were treated with 200 and 100 mg/kg PNS respectively per day and the huperzine A group was treated with 0.3 mg/kg huperzine A per day, all by intragastric administration for 8 consecutive weeks. The same volume of double distilled water was given to the control group. The activity of a-secretase was assayed by direct immunofluorescent method(DIF). Western blot was used to detect the content of alpha-secretase including [[ADAM9]], [[ADAM10]] and [[ADAM17]] proteins. The Relative Fluorescence Units (RFU) of PNS high-dosage and low-dosage groups were higher than that of control group (P < 0.01). The results of western blot showed that the level of [[ADAM9]] protein expression in PNS high-dosage, low-dosage and huperzine A groups was significantly higher than that of control group (P < 0.05) while the levels of [[ADAM10]] protein expression in PNS high-dosage, low-dosage and huperzine A groups was significantly lower than that of control group (P < 0.05), while level of [[ADAM17]] of huperzine A group was higher than that of control group (P < 0.05). PNS can increase activity of alpha-secretase in the brain of SAMP8 mouse via increasing the level of [[ADAM9]] protein expression.
|mesh-terms=* ADAM Proteins
* ADAM10 Protein
* ADAM17 Protein
* Aging
* Alzheimer Disease
* Amyloid Precursor Protein Secretases
* Amyloid beta-Protein Precursor
* Animals
* Blotting, Western
* Brain
* Disease Models, Animal
* Female
* Gene Expression Regulation, Enzymologic
* Membrane Proteins
* Mice
* Panax notoginseng
* Random Allocation
* Saponins


}}
{{medline-entry
|title=Endothelial deletion of [[ADAM17]] in mice results in defective remodeling of the semilunar valves and cardiac dysfunction in adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23354118
|abstract=Global inactivation of the metalloproteinase [[ADAM17]] during mouse development results in perinatal lethality and abnormalities of the heart, including late embryonic cardiomegaly and thickened semilunar and atrioventricular valves. These defects have been attributed in part to a lack of [[ADAM17]]-mediated processing of HB-[[EGF]], as absence of soluble HB-[[EGF]] results in similar phenotypes. Because valvular mesenchymal cells are largely derived from cardiac endothelial cells, we generated mice with a floxed Adam17 allele and crossed these animals with Tie2-Cre transgenics to focus on the role of endothelial [[ADAM17]] in valvulogenesis. We find that although hearts from late-stage embryos with ablation of endothelial [[ADAM17]] appear normal, an increase in valve size and cell number is evident, but only in the semilunar cusps. Unlike Hbegf(-/-) valves, [[ADAM17]]-null semilunar valves do not differ from controls in acute cell proliferation at embryonic day 14.5 (E14.5), suggesting compensatory processing of HB-[[EGF]]. However, levels of the proteoglycan versican are significantly reduced in mutant hearts early in valve remodeling (E12.5). After birth, aortic valve cusps from mutants are not only hyperplastic but also show expansion of the glycosaminoglycan-rich component, with the majority of adults exhibiting aberrant compartmentalization of versican and increased deposition of collagen. The inability of mutant outflow valve precursors to transition into fully mature cusps is associated with decreased postnatal viability, progressive cardiomegaly, and systolic dysfunction. Together, our data indicate that [[ADAM17]] is required in valvular endothelial cells for regulating cell content as well as extracellular matrix composition and organization in semilunar valve remodeling and homeostasis.
|mesh-terms=* ADAM Proteins
* ADAM17 Protein
* Aging
* Animals
* Animals, Newborn
* Aortic Valve Stenosis
* Apoptosis
* Cardiomegaly
* Cell Proliferation
* Collagen
* Crosses, Genetic
* Electrocardiography
* Embryo, Mammalian
* Endothelial Cells
* Extracellular Matrix
* Female
* Gene Deletion
* Heart Valves
* Heparin-binding EGF-like Growth Factor
* Hyaluronic Acid
* Integrases
* Intercellular Signaling Peptides and Proteins
* Male
* Mice
* Receptor, TIE-2
* Survival Analysis
* Systole
* Versicans

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3622831
}}
{{medline-entry
|title=Expression analysis of [[ADAM17]] during mouse eye development.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/22055939
|abstract=[[ADAM17]] (a disintegrin and metallopeptidase domain 17) is crucial for eye morphogenesis. In this study we analysed the expression pattern of [[ADAM17]] during mouse eye development. [[ADAM17]] expression in adult retina was examined using the reverse transcription-polymerase chain reaction (RT-PCR) and verification of the RT-PCR products by DNA sequencing. Immunohistochemistry was performed to evaluate the [[ADAM17]] expression pattern in mouse eyes at developmental stages of embryonic day (E) 12, E14, E16, E18, postnatal day (P) 0, P1, P4, P7, P14, P 30 and P175 (adult). We detected [[ADAM17]] mRNA in adult retina tissue. [[ADAM17]] protein was expressed in non-pigmented ciliary epithelial cells and in retinal vessels from P7 onwards during eye development. In corneal epithelial cells and endothelium, [[ADAM17]] protein was present from P14 onwards. Although, mice in which the functional [[ADAM17]] gene is significantly reduced develop multiple eye malformations, the expression of [[ADAM17]] is not ubiquitous over the entire eye. Its expression pattern during development suggests that not only [[TNF]]-alpha but additional membrane-anchored substrates of [[ADAM17]] play an important role in eye formation.
|mesh-terms=* ADAM Proteins
* ADAM17 Protein
* Aging
* Animals
* Embryonic Development
* Female
* Gene Expression Regulation, Developmental
* Male
* Mice
* Retina
* Tissue Distribution

|full-text-url=https://sci-hub.do/10.1016/j.aanat.2011.10.008
}}
{{medline-entry
|title=Myeloid-derived suppressor cells down-regulate L-selectin expression on CD4  and CD8  T cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/19553533
|abstract=Effective cell-mediated antitumor immunity requires the activation of tumor-reactive T cells and the trafficking of activated T cells to tumor sites. These processes involve the extravasation of lymphocytes from the blood and lymphatics, and their homing to lymph nodes and tumors. L-selectin (CD62L) is an important molecule in these processes. It directs naive lymphocytes to peripheral lymph nodes where they become activated and it traffics naive lymphocytes to inflammatory environments, such as tumors. Individuals with advanced cancer are immune suppressed due to myeloid-derived suppressor cells (MDSC), a population of immature myeloid cells that accumulate to high levels in response to tumor-secreted and proinflammatory factors. We now demonstrate that the reduction in T cell levels of L-selectin that is commonly seen in individuals with cancer inversely correlates with MDSC levels. Three lines of evidence demonstrate that MDSC directly down-regulate L-selectin on naive T cells: 1) naive T cells cocultured with tumor-induced MDSC have reduced L-selectin; 2) T cells in tumor-free aged mice with elevated levels of MDSC have reduced L-selectin, and 3) peritoneal exudate T cells of tumor-free mice treated with plasminogen activator urokinase to elevate MDSC have reduced levels of L-selectin. MDSC are likely to down-regulate L-selectin through their plasma membrane expression of [[ADAM17]] (a disintegrin and metalloproteinase domain 17), an enzyme that cleaves the ectodomain of L-selectin. Therefore, MDSC down-regulate L-selectin levels on naive T cells, decreasing their ability to home to sites where they would be activated. This is another mechanism by which MDSC inhibit antitumor immunity.
|mesh-terms=* ADAM Proteins
* ADAM17 Protein
* Aging
* Animals
* CD4-Positive T-Lymphocytes
* CD8-Positive T-Lymphocytes
* Cell Line, Tumor
* Cell Movement
* Coculture Techniques
* Down-Regulation
* Immunity, Cellular
* L-Selectin
* Mice
* Mice, Inbred BALB C
* Myeloid Cells
* Neoplasms, Experimental
* Paracrine Communication
* Urokinase-Type Plasminogen Activator

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2800824
}}