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Article ; Online: Opposing USP19 splice variants in TGF-β signaling and TGF-β-induced epithelial-mesenchymal transition of breast cancer cells

Zhang, Jing / van Dinther, Maarten / Thorikay, Midory / Gourabi, Babak Mousavi / Kruithof, Boudewijn P. T. / Dijke, Peter ten

Cell. Mol. Life Sci.. 2023 Feb., v. 80, no. 2 p.43-43

2023

Abstract: Ubiquitin-specific protease (USP)19 is a deubiquitinating enzyme that regulates the stability and function of multiple proteins, thereby controlling various biological responses. The alternative splicing of USP19 results in the expression of two major ... ...

Abstract	Ubiquitin-specific protease (USP)19 is a deubiquitinating enzyme that regulates the stability and function of multiple proteins, thereby controlling various biological responses. The alternative splicing of USP19 results in the expression of two major encoded variants that are localized to the endoplasmic reticulum (ER) (USP19-ER) and cytoplasm (USP19-CY). The importance of alternative splicing for the function of USP19 remains unclear. Here, we demonstrated that USP19-CY promotes TGF-β signaling by directly interacting with TGF-β type I receptor (TβRI) and protecting it from degradation at the plasma membrane. In contrast, USP19-ER binds to and sequesters TβRI in the ER. By decreasing cell surface TβRI levels, USP19-ER inhibits TGF-β/SMAD signaling in a deubiquitination-independent manner. Moreover, USP19-ER inhibits TGF-β-induced epithelial-mesenchymal transition (EMT), whereas USP19-CY enhances EMT, as well as the migration and extravasation of breast cancer cells. Furthermore, USP19-CY expression is correlated with poor prognosis and is higher in breast cancer tissues than in adjacent normal tissues. Notably, the splicing modulator herboxidiene inhibits USP19-CY, increases USP19-ER expression and suppresses breast cancer cell migration. Targeting USP19 splicing or its deubiquitinating activity may have potential therapeutic effects on breast cancer.
Keywords	breast neoplasms ; cell movement ; endoplasmic reticulum ; neoplasm cells ; plasma membrane ; prognosis ; proteinases ; therapeutics
Language	English
Dates of publication	2023-02
Size	p. 43.
Publishing place	Springer International Publishing
Document type	Article ; Online
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-022-04672-w
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Opposing USP19 splice variants in TGF-β signaling and TGF-β-induced epithelial-mesenchymal transition of breast cancer cells.

Zhang, Jing / van Dinther, Maarten / Thorikay, Midory / Gourabi, Babak Mousavi / Kruithof, Boudewijn P T / Ten Dijke, Peter

Cellular and molecular life sciences : CMLS

2023 Volume 80, Issue 2, Page(s) 43

Abstract	Ubiquitin-specific protease (USP)19 is a deubiquitinating enzyme that regulates the stability and function of multiple proteins, thereby controlling various biological responses. The alternative splicing of USP19 results in the expression of two major encoded variants that are localized to the endoplasmic reticulum (ER) (USP19-ER) and cytoplasm (USP19-CY). The importance of alternative splicing for the function of USP19 remains unclear. Here, we demonstrated that USP19-CY promotes TGF-β signaling by directly interacting with TGF-β type I receptor (TβRI) and protecting it from degradation at the plasma membrane. In contrast, USP19-ER binds to and sequesters TβRI in the ER. By decreasing cell surface TβRI levels, USP19-ER inhibits TGF-β/SMAD signaling in a deubiquitination-independent manner. Moreover, USP19-ER inhibits TGF-β-induced epithelial-mesenchymal transition (EMT), whereas USP19-CY enhances EMT, as well as the migration and extravasation of breast cancer cells. Furthermore, USP19-CY expression is correlated with poor prognosis and is higher in breast cancer tissues than in adjacent normal tissues. Notably, the splicing modulator herboxidiene inhibits USP19-CY, increases USP19-ER expression and suppresses breast cancer cell migration. Targeting USP19 splicing or its deubiquitinating activity may have potential therapeutic effects on breast cancer.
MeSH term(s)	Humans ; Female ; Transforming Growth Factor beta/genetics ; Transforming Growth Factor beta/metabolism ; Epithelial-Mesenchymal Transition/genetics ; Breast Neoplasms/metabolism ; Receptors, Transforming Growth Factor beta/genetics ; Receptors, Transforming Growth Factor beta/metabolism ; Cell Membrane/metabolism ; Cell Movement/genetics ; Cell Line, Tumor ; Endopeptidases/metabolism
Chemical Substances	Transforming Growth Factor beta ; Receptors, Transforming Growth Factor beta ; USP19 protein, human (EC 3.4.-) ; Endopeptidases (EC 3.4.-)
Language	English
Publishing date	2023-01-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-022-04672-w
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Article ; Online: Immunofluorescent Visualization of BMP Signaling Activation on Paraffin-Embedded Tissue Sections.

Alkema, Maaike / Goumans, Marie-José / Kruithof, Boudewijn P T

Methods in molecular biology (Clifton, N.J.)

2018 Volume 1891, Page(s) 191–200

Abstract: Immunohistochemistry allows the detection of the presence, localization, and activation of proteins in biological tissues by using the ability of antibodies to bind to specific antigens. Cellular signaling can be visualized using antibodies raised ... ...

Abstract	Immunohistochemistry allows the detection of the presence, localization, and activation of proteins in biological tissues by using the ability of antibodies to bind to specific antigens. Cellular signaling can be visualized using antibodies raised against phosphorylated proteins. Phosphorylated Smad1, Smad5, and Smad9 are the activated signaling molecules of the BMP pathway that transfer BMP signals from the cell surface to the nucleus. Here we describe the detection of phospho-Smad1/5/9 on paraformaldehyde-fixed and paraffin-embedded tissue sections by immunofluorescence.
MeSH term(s)	Bone Morphogenetic Proteins/metabolism ; Fluorescent Antibody Technique ; Immunohistochemistry ; Signal Transduction
Chemical Substances	Bone Morphogenetic Proteins
Language	English
Publishing date	2018-11-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-8904-1_14
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Article ; Online: Superimposed Tissue Formation in Human Aortic Valve Disease: Differences between Regurgitant and Stenotic Valves.

Kruithof, Boudewijn P T / van Wijngaarden, Aniek L / Mousavi Gourabi, Babak / Hjortnaes, Jesper / Palmen, Meindert / Ajmone Marsan, Nina

Journal of cardiovascular development and disease

2021 Volume 8, Issue 7

Abstract: The formation of superimposed tissue (SIT), a layer on top of the original valve leaflet, has been described in patients with mitral regurgitation as a major contributor to valve thickening and possibly as a result of increased mechanical stresses. ... ...

Abstract	The formation of superimposed tissue (SIT), a layer on top of the original valve leaflet, has been described in patients with mitral regurgitation as a major contributor to valve thickening and possibly as a result of increased mechanical stresses. However, little is known whether SIT formation also occurs in aortic valve disease. We therefore performed histological analyses to assess SIT formation in aortic valve leaflets (
Language	English
Publishing date	2021-07-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2777082-5
ISSN	2308-3425 ; 2308-3425
ISSN (online)	2308-3425
ISSN	2308-3425
DOI	10.3390/jcdd8070079
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Article ; Online: Characterization of Degenerative Mitral Valve Disease: Differences between Fibroelastic Deficiency and Barlow's Disease.

van Wijngaarden, Aniek L / Kruithof, Boudewijn P T / Vinella, Tommaso / Barge-Schaapveld, Daniela Q C M / Ajmone Marsan, Nina

Journal of cardiovascular development and disease

2021 Volume 8, Issue 2

Abstract: Degenerative mitral valve disease causing mitral valve prolapse is the most common cause of primary mitral regurgitation, with two distinct phenotypes generally recognized with some major differences, i.e., fibroelastic deficiency (FED) and Barlow's ... ...

Abstract	Degenerative mitral valve disease causing mitral valve prolapse is the most common cause of primary mitral regurgitation, with two distinct phenotypes generally recognized with some major differences, i.e., fibroelastic deficiency (FED) and Barlow's disease. The aim of this review was to describe the main histological, clinical and echocardiographic features of patients with FED and Barlow's disease, highlighting the differences in diagnosis, risk stratification and patient management, but also the still significant gaps in understanding the exact pathophysiology of these two phenotypes.
Language	English
Publishing date	2021-02-22
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2777082-5
ISSN	2308-3425 ; 2308-3425
ISSN (online)	2308-3425
ISSN	2308-3425
DOI	10.3390/jcdd8020023
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Article ; Online: Cardiac endothelial cells express Wilms' tumor-1: Wt1 expression in the developing, adult and infarcted heart.

Duim, Sjoerd N / Kurakula, Kondababu / Goumans, Marie-José / Kruithof, Boudewijn P T

Journal of molecular and cellular cardiology

2015 Volume 81, Page(s) 127–135

Abstract: Myocardial infarction is the leading cause of death worldwide. Due to their limited regenerative capacity lost cardiomyocytes are replaced by a non-contractile fibrotic scar tissue. The epicardial layer of the heart provides cardiac progenitor cells ... ...

Abstract	Myocardial infarction is the leading cause of death worldwide. Due to their limited regenerative capacity lost cardiomyocytes are replaced by a non-contractile fibrotic scar tissue. The epicardial layer of the heart provides cardiac progenitor cells during development. Because this layer regains embryonic characteristics in the adult heart after cardiac injury, it could serve as a promising source for resident cardiac progenitor cells. Wilms' tumor-1 (Wt1) is associated with the activation and reactivation of the epicardium and therefore potentially important for the differentiation and regenerative capacity of the epicardium. To gain more insight into the regulation of Wt1 we examined the spatiotemporal expression pattern of Wt1 during murine development and after cardiac injury. Interestingly, we found that Wt1 is expressed in the majority of the cardiac endothelial cells within the myocardial ventricular layer of the developing heart from E12.5 onwards. In the adult heart only a subset of coronary endothelial cells remains positive for Wt1. After myocardial infarction Wt1 is temporally upregulated in the endothelial cells of the infarcted area and the border zone of the heart. In vitro experiments show that endothelial Wt1 expression can be induced by hypoxia. We show that Wt1 is associated with endothelial cell proliferation: Wt1 expression is higher in proliferating endothelial cells, Wt1 knockdown inhibits the proliferation of endothelial cells, and Wt1 regulates CyclinD1 expression. Finally, endothelial cells lacking Wt1 are not capable to establish a proper vascular network in vitro. Together, these results suggest a possible role for Wt1 in cardiac vessel formation in development and disease.
MeSH term(s)	Animals ; Cell Hypoxia ; Cell Movement ; Cell Proliferation ; Collagen/chemistry ; Coronary Vessels/metabolism ; Coronary Vessels/pathology ; Cyclin D1/genetics ; Cyclin D1/metabolism ; Drug Combinations ; Embryo, Mammalian ; Endothelial Cells/metabolism ; Endothelial Cells/pathology ; Female ; Gene Expression Regulation, Developmental ; Laminin/chemistry ; Mice ; Mice, Inbred C57BL ; Myocardial Infarction/genetics ; Myocardial Infarction/metabolism ; Myocardial Infarction/pathology ; Myocardium/metabolism ; Myocardium/pathology ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Pericardium/metabolism ; Pericardium/pathology ; Proteoglycans/chemistry ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Signal Transduction ; Stem Cells/metabolism ; Stem Cells/pathology
Chemical Substances	Ccnd1 protein, mouse ; Drug Combinations ; Laminin ; Proteoglycans ; Repressor Proteins ; WT1 protein, mouse ; matrigel (119978-18-6) ; Cyclin D1 (136601-57-5) ; Collagen (9007-34-5)
Language	English
Publishing date	2015-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80157-4
ISSN	1095-8584 ; 0022-2828
ISSN (online)	1095-8584
ISSN	0022-2828
DOI	10.1016/j.yjmcc.2015.02.007
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Article: In vivo

Bax, Noortje A M / Duim, Sjoerd N / Kruithof, Boudewijn P T / Smits, Anke M / Bouten, Carlijn V C / Goumans, Marie José

Frontiers in cardiovascular medicine

2019 Volume 6, Page(s) 81

Abstract: Human epicardium-derived cells (hEPDCs) transplanted in the NOD-SCID mouse heart after myocardial infarction (MI) are known to improve cardiac function, most likely orchestrated by paracrine mechanisms that limit adverse remodeling. It is not yet known, ... ...

Abstract	Human epicardium-derived cells (hEPDCs) transplanted in the NOD-SCID mouse heart after myocardial infarction (MI) are known to improve cardiac function, most likely orchestrated by paracrine mechanisms that limit adverse remodeling. It is not yet known, however, if hEPDCs contribute to preservation of cardiac function via the secretion of matrix proteins and/or matrix proteases to reduce scar formation. This study describes the ability of hEPDCs to produce human collagen type I after transplantation into the infarct border zone, thereby creating their own extracellular environment. As the
Language	English
Publishing date	2019-06-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2781496-8
ISSN	2297-055X
ISSN	2297-055X
DOI	10.3389/fcvm.2019.00081
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Article ; Online: Stress-induced remodelling of the mitral valve: a model for leaflet thickening and superimposed tissue formation in mitral valve disease.

Kruithof, Boudewijn P T / Paardekooper, Laura / Hiemstra, Yasmine L / Goumans, Marie-José / Palmen, Meindert / Delgado, Victoria / Klautz, Robert J M / Ajmone Marsan, Nina

Cardiovascular research

2019 Volume 116, Issue 5, Page(s) 931–943

Abstract: Aims: In mitral valve prolapse (MVP), leaflet thickening has recently been suggested to be due, in addition to a myxomatous degeneration, to the presence of a superimposed tissue (SIT), defined as an additional fibrous layer on top of the original ... ...

Abstract	Aims: In mitral valve prolapse (MVP), leaflet thickening has recently been suggested to be due, in addition to a myxomatous degeneration, to the presence of a superimposed tissue (SIT), defined as an additional fibrous layer on top of the original leaflet. The mechanisms of SIT formation are currently unknown. We hypothesized that SIT formation would result from excessive leaflet stress and we used a unique ex vivo model to assess the correlation between leaflet remodelling and the type and location of mechanical stress and to elucidate the mechanisms underlying SIT formation. Methods and results: Human diseased mitral valves (MVs; n = 21) were histologically analysed for SIT formation and original leaflet thickening. The SIT comprised of various compositions of extracellular matrix and could reach more than 50% of total leaflet thickness. Original leaflet and SIT thickness did not show significant correlation (r = -0.27, P = 0.23), suggesting different regulatory mechanisms. To study the role of the mechanical environment on MV remodelling, mouse MV were cultured in their natural position in the heart and subjected to various haemodynamic conditions representing specific phases of the cardiac cycle and the MVP configuration. SIT formation was induced in the ex vivo model, mostly present on the atrial side, and clearly dependent on the duration, type, and extent of mechanical stress. Specific stainings and lineage tracing experiments showed that SIT comprises of macrophages and myofibroblasts and is associated with the activation of the transforming growth factor-beta and bone morphogenetic protein signalling pathways. Migration of valvular interstitial cells and macrophages through breakages of the endothelial cell lining contributed to SIT formation. Conclusions: Mechanical stresses induce specific cellular and molecular changes in the MV that result in SIT formation. These observations provide the first insights in the mechanism of SIT formation and represent an initial step to identify potential novel and early treatment for MVP.
MeSH term(s)	Aged ; Animals ; Bone Morphogenetic Proteins/metabolism ; Cell Movement ; Endothelial Cells/metabolism ; Endothelial Cells/pathology ; Female ; Hemodynamics ; Humans ; Macrophages/metabolism ; Macrophages/pathology ; Male ; Mechanotransduction, Cellular ; Mice, Transgenic ; Middle Aged ; Mitral Valve/metabolism ; Mitral Valve/pathology ; Mitral Valve/physiopathology ; Mitral Valve Insufficiency/metabolism ; Mitral Valve Insufficiency/pathology ; Mitral Valve Insufficiency/physiopathology ; Mitral Valve Prolapse/metabolism ; Mitral Valve Prolapse/pathology ; Mitral Valve Prolapse/physiopathology ; Phosphorylation ; Smad Proteins/metabolism ; Stress, Mechanical ; Time Factors ; Tissue Culture Techniques ; Transforming Growth Factor beta/metabolism
Chemical Substances	Bone Morphogenetic Proteins ; Smad Proteins ; Transforming Growth Factor beta
Language	English
Publishing date	2019-09-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80340-6
ISSN	1755-3245 ; 0008-6363
ISSN (online)	1755-3245
ISSN	0008-6363
DOI	10.1093/cvr/cvz204
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Article ; Online: Oncofetal Protein CRIPTO Is Involved in Wound Healing and Fibrogenesis in the Regenerating Liver and Is Associated with the Initial Stages of Cardiac Fibrosis.

Karkampouna, Sofia / van der Helm, Danny / Scarpa, Mario / van Hoek, Bart / Verspaget, Hein W / Goumans, Marie-Jose / Coenraad, Minneke J / Kruithof, Boudewijn P T / Kruithof-de Julio, Marianna

Cells

2021 Volume 10, Issue 12

Abstract: Oncofetal protein, CRIPTO, is silenced during homeostatic postnatal life and often re-expressed in different neoplastic processes, such as hepatocellular carcinoma. Given the reactivation of CRIPTO in pathological conditions reported in various adult ... ...

Abstract	Oncofetal protein, CRIPTO, is silenced during homeostatic postnatal life and often re-expressed in different neoplastic processes, such as hepatocellular carcinoma. Given the reactivation of CRIPTO in pathological conditions reported in various adult tissues, the aim of this study was to explore whether CRIPTO is expressed during liver fibrogenesis and whether this is related to the disease severity and pathogenesis of fibrogenesis. Furthermore, we aimed to identify the impact of CRIPTO expression on fibrogenesis in organs with high versus low regenerative capacity, represented by murine liver fibrogenesis and adult murine heart fibrogenesis. Circulating CRIPTO levels were measured in plasma samples of patients with cirrhosis registered at the waitlist for liver transplantation (LT) and 1 year after LT. The expression of CRIPTO and fibrotic markers (αSMA, collagen type I) was determined in human liver tissues of patients with cirrhosis (on a basis of viral hepatitis or alcoholic disease), in cardiac tissue samples of patients with end-stage heart failure, and in mice with experimental liver and heart fibrosis using immuno-histochemical stainings and qPCR. Mouse models with experimental chronic liver fibrosis, induced with multiple shots of carbon tetrachloride (CCl
MeSH term(s)	Adenoviridae/metabolism ; Animals ; Cell Proliferation ; Collagen/metabolism ; Disease Models, Animal ; End Stage Liver Disease/metabolism ; Epidermal Growth Factor/metabolism ; Fibrosis ; GPI-Linked Proteins/metabolism ; Hepatocytes/metabolism ; Hepatocytes/pathology ; Intercellular Signaling Peptides and Proteins/metabolism ; Ligands ; Liver Cirrhosis/metabolism ; Liver Cirrhosis/pathology ; Liver Regeneration ; Male ; Membrane Glycoproteins/metabolism ; Mice, Inbred C57BL ; Myocardium/metabolism ; Myocardium/pathology ; Neoplasm Proteins/metabolism ; Up-Regulation ; Wound Healing ; Mice
Chemical Substances	GPI-Linked Proteins ; Intercellular Signaling Peptides and Proteins ; Ligands ; Membrane Glycoproteins ; Neoplasm Proteins ; TDGF1 protein, human ; Tdgf1 protein, mouse ; Epidermal Growth Factor (62229-50-9) ; Collagen (9007-34-5)
Language	English
Publishing date	2021-11-26
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10123325
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Article ; Online: New calcification model for intact murine aortic valves.

Kruithof, Boudewijn P T / van de Pol, Vera / Los, Tamara / Lodder, Kirsten / Mousavi Gourabi, Babak / DeRuiter, Marco C / Goumans, Marie-José / Ajmone Marsan, Nina

Journal of molecular and cellular cardiology

2021 Volume 156, Page(s) 95–104

Abstract: Calcific aortic valve disease (CAVD) is a common progressive disease of the aortic valves, for which no medical treatment exists and surgery represents currently the only therapeutic solution. The development of novel pharmacological treatments for CAVD ... ...

Abstract	Calcific aortic valve disease (CAVD) is a common progressive disease of the aortic valves, for which no medical treatment exists and surgery represents currently the only therapeutic solution. The development of novel pharmacological treatments for CAVD has been hampered by the lack of suitable test-systems, which require the preservation of the complex valve structure in a mechanically and biochemical controllable system. Therefore, we aimed at establishing a model which allows the study of calcification in intact mouse aortic valves by using the Miniature Tissue Culture System (MTCS), an ex vivo flow model for whole mouse hearts. Aortic valves of wild-type mice were cultured in the MTCS and exposed to osteogenic medium (OSM, containing ascorbic acid, β-glycerophosphate and dexamethasone) or inorganic phosphates (PI). Osteogenic calcification occurred in the aortic valve leaflets that were cultured ex vivo in the presence of PI, but not of OSM. In vitro cultured mouse and human valvular interstitial cells calcified in both OSM and PI conditions, revealing in vitro-ex vivo differences. Furthermore, endochondral differentiation occurred in the aortic root of ex vivo cultured mouse hearts near the hinge of the aortic valve in both PI and OSM conditions. Dexamethasone was found to induce endochondral differentiation in the aortic root, but to inhibit calcification and the expression of osteogenic markers in the aortic leaflet, partly explaining the absence of calcification in the aortic valve cultured with OSM. The osteogenic calcifications in the aortic leaflet and the endochondral differentiation in the aortic root resemble calcifications found in human CAVD. In conclusion, we have established an ex vivo calcification model for intact wild-type murine aortic valves in which the initiation and progression of aortic valve calcification can be studied. The in vitro-ex vivo differences found in our studies underline the importance of ex vivo models to facilitate pre-clinical translational studies.
MeSH term(s)	Animals ; Aortic Valve/metabolism ; Aortic Valve/pathology ; Aortic Valve Stenosis/etiology ; Aortic Valve Stenosis/metabolism ; Aortic Valve Stenosis/pathology ; Biomarkers ; Calcification, Physiologic/drug effects ; Calcinosis/etiology ; Calcinosis/metabolism ; Calcinosis/pathology ; Cell Culture Techniques ; Cell Differentiation/drug effects ; Cell Differentiation/genetics ; Cells, Cultured ; Dexamethasone/pharmacology ; Disease Susceptibility ; Endothelial Cells/metabolism ; Humans ; Mice ; Osteogenesis/drug effects ; Osteogenesis/genetics ; Tissue Culture Techniques
Chemical Substances	Biomarkers ; Dexamethasone (7S5I7G3JQL)
Language	English
Publishing date	2021-03-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80157-4
ISSN	1095-8584 ; 0022-2828
ISSN (online)	1095-8584
ISSN	0022-2828
DOI	10.1016/j.yjmcc.2021.03.003
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