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Article ; Online: Linking Clinical Parameters and Genotype in Dilated Cardiomyopathy.

Churko, Jared M

2018 Volume 11, Issue 11, Page(s) e005459

MeSH term(s)	Cardiomyopathies ; Cardiomyopathy, Dilated ; Genotype ; Heart Failure ; Humans ; Phenotype ; Ventricular Function, Left
Language	English
Publishing date	2018-11-05
Publishing country	United States
Document type	Editorial ; Comment
ZDB-ID	2429459-7
ISSN	1941-3297 ; 1941-3289
ISSN (online)	1941-3297
ISSN	1941-3289
DOI	10.1161/CIRCHEARTFAILURE.118.005459
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Zs.A 6745: Show issues

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Article ; Online: Tissue Engineering Techniques for Induced Pluripotent Stem Cell Derived Three-Dimensional Cardiac Constructs.

Salem, Tori / Frankman, Zachary / Churko, Jared M

Tissue engineering. Part B, Reviews

2021 Volume 28, Issue 4, Page(s) 891–911

Abstract: Recent developments in applied developmental physiology have provided well-defined methodologies for producing human stem cell derived cardiomyocytes. The cardiomyocytes produced have become commonplace as cardiac physiology research models. ... ...

Abstract	Recent developments in applied developmental physiology have provided well-defined methodologies for producing human stem cell derived cardiomyocytes. The cardiomyocytes produced have become commonplace as cardiac physiology research models. Accessibility has also allowed for the development of tissue engineered human heart constructs for drug screening, surgical intervention, and investigating cardiac pathogenesis. However, cardiac tissue engineering is an interdisciplinary field that involves complex engineering and physiological concepts, which limits its accessibility. Our review provides a readable, broad reaching, and thorough discussion of major factors to consider for the development of cardiovascular tissues from stem cell derived cardiomyocytes. In this study, our review will examine important considerations in undertaking a cardiovascular tissue engineering project and will present, interpret, and summarize some of the recent advancements in this field. Throughout, we review different forms of tissue engineered constructs, a discussion on cardiomyocyte sources, and an in-depth discussion of the fabrication and maturation procedures for tissue engineered heart constructs. Impact statement With advancements in cardiac differentiation protocols, the production of human induced pluripotent stem cell derived cardiomyocytes is becoming cost effective and routine in the laboratory setting. Monolayer based culture methods are rapidly being replaced by three-dimensional (3D) tissue engineered constructs, which are more representative of the heart geometry. In the review presented, we delve into important concepts and tissue engineering principles that should be considered when generating 3D cardiac constructs, interpreting data acquired from, and embarking on a 3D cardiac tissue-based research project.
MeSH term(s)	Cell Differentiation ; Drug Evaluation, Preclinical ; Humans ; Induced Pluripotent Stem Cells ; Myocytes, Cardiac ; Tissue Engineering/methods
Language	English
Publishing date	2021-11-23
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2420584-9
ISSN	1937-3376 ; 1937-3368
ISSN (online)	1937-3376
ISSN	1937-3368
DOI	10.1089/ten.TEB.2021.0088
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Article ; Online: Generation of an iPSC line from a Pontocerebellar Hypoplasia 1B patient harboring a homozygous c.395 A > C mutation in EXOSC3 along with a family matched control.

Stansfield, Ben N / Rangasamy, Sampath / Ramsey, Keri / Khanna, May / Churko, Jared M

Stem cell research

2022 Volume 65, Page(s) 102944

Abstract: Pontocerebellar Hypoplasia 1B (PCH1B) is a severe autosomal recessive neurological disorder that is associated with mutations in the exosome complex component RRP40 (EXOSC3) gene. We generated and characterized an iPSC line from an individual with PCH1B ... ...

Abstract	Pontocerebellar Hypoplasia 1B (PCH1B) is a severe autosomal recessive neurological disorder that is associated with mutations in the exosome complex component RRP40 (EXOSC3) gene. We generated and characterized an iPSC line from an individual with PCH1B that harbors a recessive homozygous c.395 A > C mutation in EXOSC3 and a family matched control from the probands unaffected mother. Each iPSC line presents with normal morphology and karyotype and express high levels of pluripotent markers. UAZTi009-A and UAZTi011-A are capable of directed differentiation and can be used as a vital experimental tool to study the development of PCH1B.
MeSH term(s)	Humans ; Mutation/genetics ; RNA-Binding Proteins ; Exosome Multienzyme Ribonuclease Complex
Chemical Substances	EXOSC3 protein, human ; RNA-Binding Proteins ; Exosome Multienzyme Ribonuclease Complex (EC 3.1.-)
Language	English
Publishing date	2022-10-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2393143-7
ISSN	1876-7753 ; 1873-5061
ISSN (online)	1876-7753
ISSN	1873-5061
DOI	10.1016/j.scr.2022.102944
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Article ; Online: Gap junction remodeling in skin repair following wounding and disease.

Churko, Jared M / Laird, Dale W

Physiology (Bethesda, Md.)

2013 Volume 28, Issue 3, Page(s) 190–198

Abstract: In the present review, we provide an overview of connexin expression during skin development and remodeling in wound healing, and reflect on how loss- or gain-of-function connexin mutations may change cellular phenotypes and lead to diseases of the skin. ...

Abstract	In the present review, we provide an overview of connexin expression during skin development and remodeling in wound healing, and reflect on how loss- or gain-of-function connexin mutations may change cellular phenotypes and lead to diseases of the skin. We also consider the therapeutic value of targeting connexins in wound healing.
MeSH term(s)	Animals ; Cell Differentiation ; Cell Movement ; Cell Proliferation ; Connexins/genetics ; Connexins/metabolism ; Gap Junctions/metabolism ; Gap Junctions/pathology ; Genetic Predisposition to Disease ; Humans ; Mutation ; Phenotype ; Signal Transduction ; Skin/growth & development ; Skin/injuries ; Skin/metabolism ; Skin/pathology ; Skin Diseases/genetics ; Skin Diseases/metabolism ; Skin Diseases/pathology ; Wound Healing
Chemical Substances	Connexins
Language	English
Publishing date	2013-05
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2158667-6
ISSN	1548-9221 ; 1548-9213
ISSN (online)	1548-9221
ISSN	1548-9213
DOI	10.1152/physiol.00058.2012
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Article ; Online: Epicardial placement of human placental membrane protects from heart injury in a swine model of myocardial infarction.

Skaria, Rinku S / Lopez-Pier, Marissa A / Kathuria, Brij S / Leber, Christian J / Langlais, Paul R / Aras, Shravan G / Khalpey, Zain I / Hitscherich, Pamela G / Chnari, Evangelia / Long, Marc / Churko, Jared M / Runyan, Raymond B / Konhilas, John P

Physiological reports

2023 Volume 11, Issue 20, Page(s) e15838

Abstract: Cardiac ischemic reperfusion injury (IRI) is paradoxically instigated by reestablishing blood-flow to ischemic myocardium typically from a myocardial infarction (MI). Although revascularization following MI remains the standard of care, effective ... ...

Abstract	Cardiac ischemic reperfusion injury (IRI) is paradoxically instigated by reestablishing blood-flow to ischemic myocardium typically from a myocardial infarction (MI). Although revascularization following MI remains the standard of care, effective strategies remain limited to prevent or attenuate IRI. We hypothesized that epicardial placement of human placental amnion/chorion (HPAC) grafts will protect against IRI. Using a clinically relevant model of IRI, swine were subjected to 45 min percutaneous ischemia followed with (MI + HPAC, n = 3) or without (MI only, n = 3) HPAC. Cardiac function was assessed by echocardiography, and regional punch biopsies were collected 14 days post-operatively. A deep phenotyping approach was implemented by using histological interrogation and incorporating global proteomics and transcriptomics in nonischemic, ischemic, and border zone biopsies. Our results established HPAC limited the extent of cardiac injury by 50% (11.0 ± 2.0% vs. 22.0 ± 3.0%, p = 0.039) and preserved ejection fraction in HPAC-treated swine (46.8 ± 2.7% vs. 35.8 ± 4.5%, p = 0.014). We present comprehensive transcriptome and proteome profiles of infarct (IZ), border (BZ), and remote (RZ) zone punch biopsies from swine myocardium during the proliferative cardiac repair phase 14 days post-MI. Both HPAC-treated and untreated tissues showed regional dynamic responses, whereas only HPAC-treated IZ revealed active immune and extracellular matrix remodeling. Decreased endoplasmic reticulum (ER)-dependent protein secretion and increased antiapoptotic and anti-inflammatory responses were measured in HPAC-treated biopsies. We provide quantitative evidence HPAC reduced cardiac injury from MI in a preclinical swine model, establishing a potential new therapeutic strategy for IRI. Minimizing the impact of MI remains a central clinical challenge. We present a new strategy to attenuate post-MI cardiac injury using HPAC in a swine model of IRI. Placement of HPAC membrane on the heart following MI minimizes ischemic damage, preserves cardiac function, and promotes anti-inflammatory signaling pathways.
MeSH term(s)	Pregnancy ; Swine ; Humans ; Female ; Animals ; Placenta/metabolism ; Myocardial Infarction/pathology ; Myocardium/metabolism ; Heart Injuries/drug therapy ; Heart Injuries/metabolism ; Heart Injuries/pathology ; Anti-Inflammatory Agents/therapeutic use ; Disease Models, Animal
Chemical Substances	Anti-Inflammatory Agents
Language	English
Publishing date	2023-10-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2724325-4
ISSN	2051-817X ; 2051-817X
ISSN (online)	2051-817X
ISSN	2051-817X
DOI	10.14814/phy2.15838
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Article ; Online: Surfaceome mapping of primary human heart cells with CellSurfer uncovers cardiomyocyte surface protein LSMEM2 and proteome dynamics in failing hearts.

Luecke, Linda Berg / Waas, Matthew / Littrell, Jack / Wojtkiewicz, Melinda / Castro, Chase / Burkovetskaya, Maria / Schuette, Erin N / Buchberger, Amanda Rae / Churko, Jared M / Chalise, Upendra / Waknitz, Michelle / Konfrst, Shelby / Teuben, Roald / Morrissette-McAlmon, Justin / Mahr, Claudius / Anderson, Daniel R / Boheler, Kenneth R / Gundry, Rebekah L

Nature cardiovascular research

2023 Volume 2, Issue 1, Page(s) 76–95

Abstract: Cardiac cell surface proteins are drug targets and useful biomarkers for discriminating among cellular phenotypes and disease states. Here we developed an analytical platform, CellSurfer, that enables quantitative cell surface proteome (surfaceome) ... ...

Abstract	Cardiac cell surface proteins are drug targets and useful biomarkers for discriminating among cellular phenotypes and disease states. Here we developed an analytical platform, CellSurfer, that enables quantitative cell surface proteome (surfaceome) profiling of cells present in limited quantities, and we apply it to isolated primary human heart cells. We report experimental evidence of surface localization and extracellular domains for 1,144
Language	English
Publishing date	2023-01-16
Publishing country	England
Document type	Journal Article
ISSN	2731-0590
ISSN (online)	2731-0590
DOI	10.1038/s44161-022-00200-y
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Article ; Online: Development of Human Pituitary Neuroendocrine Tumor Organoids to Facilitate Effective Targeted Treatments of Cushing's Disease.

Chakrabarti, Jayati / Pandey, Ritu / Churko, Jared M / Eschbacher, Jennifer / Mallick, Saptarshi / Chen, Yuliang / Hermes, Beth / Mallick, Palash / Stansfield, Ben N / Pond, Kelvin W / Thorne, Curtis A / Yuen, Kevin C J / Little, Andrew S / Zavros, Yana

Cells

2022 Volume 11, Issue 21

Abstract: 1) Background: Cushing's disease (CD) is a serious endocrine disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary neuroendocrine tumor (PitNET) that stimulates the adrenal glands to overproduce cortisol. Chronic exposure to ... ...

Abstract	(1) Background: Cushing's disease (CD) is a serious endocrine disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary neuroendocrine tumor (PitNET) that stimulates the adrenal glands to overproduce cortisol. Chronic exposure to excess cortisol has detrimental effects on health, including increased stroke rates, diabetes, obesity, cognitive impairment, anxiety, depression, and death. The first-line treatment for CD is pituitary surgery. Current surgical remission rates reported in only 56% of patients depending on several criteria. The lack of specificity, poor tolerability, and low efficacy of the subsequent second-line medical therapies make CD a medical therapeutic challenge. One major limitation that hinders the development of specific medical therapies is the lack of relevant human model systems that recapitulate the cellular composition of PitNET microenvironment. (2) Methods: human pituitary tumor tissue was harvested during transsphenoidal surgery from CD patients to generate organoids (hPITOs). (3) Results: hPITOs generated from corticotroph, lactotroph, gonadotroph, and somatotroph tumors exhibited morphological diversity among the organoid lines between individual patients and amongst subtypes. The similarity in cell lineages between the organoid line and the patient's tumor was validated by comparing the neuropathology report to the expression pattern of PitNET specific markers, using spectral flow cytometry and exome sequencing. A high-throughput drug screen demonstrated patient-specific drug responses of hPITOs amongst each tumor subtype. Generation of induced pluripotent stem cells (iPSCs) from a CD patient carrying germline mutation CDH23 exhibited dysregulated cell lineage commitment. (4) Conclusions: The human pituitary neuroendocrine tumor organoids represent a novel approach in how we model complex pathologies in CD patients, which will enable effective personalized medicine for these patients.
MeSH term(s)	Humans ; Pituitary ACTH Hypersecretion/drug therapy ; Pituitary ACTH Hypersecretion/surgery ; Pituitary Neoplasms ; Organoids ; Neuroendocrine Tumors/drug therapy ; Hydrocortisone ; Tumor Microenvironment
Chemical Substances	Hydrocortisone (WI4X0X7BPJ)
Language	English
Publishing date	2022-10-23
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11213344
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Article ; Online: Neonatal-lethal dilated cardiomyopathy due to a homozygous LMOD2 donor splice-site variant.

Yuen, Michaela / Worgan, Lisa / Iwanski, Jessika / Pappas, Christopher T / Joshi, Himanshu / Churko, Jared M / Arbuckle, Susan / Kirk, Edwin P / Zhu, Ying / Roscioli, Tony / Gregorio, Carol C / Cooper, Sandra T

European journal of human genetics : EJHG

2022 Volume 30, Issue 4, Page(s) 450–457

Abstract: Dilated cardiomyopathy (DCM) is characterized by cardiac enlargement and impaired ventricular contractility leading to heart failure. A single report identified variants in leiomodin-2 (LMOD2) as a cause of neonatally-lethal DCM. Here, we describe two ... ...

Abstract	Dilated cardiomyopathy (DCM) is characterized by cardiac enlargement and impaired ventricular contractility leading to heart failure. A single report identified variants in leiomodin-2 (LMOD2) as a cause of neonatally-lethal DCM. Here, we describe two siblings with DCM who died shortly after birth due to heart failure. Exome sequencing identified a homozygous LMOD2 variant in both siblings, (GRCh38)chr7:g.123656237G > A; NM_207163.2:c.273 + 1G > A, ablating the donor 5' splice-site of intron-1. Pre-mRNA splicing studies and western blot analysis on cDNA derived from proband cardiac tissue, MyoD-transduced proband skin fibroblasts and HEK293 cells transfected with LMOD2 gene constructs established variant-associated absence of canonically spliced LMOD2 mRNA and full-length LMOD2 protein. Immunostaining of proband heart tissue unveiled abnormally short actin-thin filaments. Our data are consistent with LMOD2 c.273 + 1G > A abolishing/reducing LMOD2 transcript expression by: (1) variant-associated perturbation in initiation of transcription due to ablation of the intron-1 donor; and/or (2) degradation of aberrant LMOD2 transcripts (resulting from use of alternative transcription start-sites or cryptic splice-sites) by nonsense-mediated decay. LMOD2 expression is critical for life and the absence of LMOD2 is associated with thin filament shortening and severe cardiac contractile dysfunction. This study describes the first splice-site variant in LMOD2 and confirms the role of LMOD2 variants in DCM.
MeSH term(s)	Actin Cytoskeleton/genetics ; Actin Cytoskeleton/metabolism ; Cardiomyopathy, Dilated/genetics ; HEK293 Cells ; Heart Failure/genetics ; Heart Failure/metabolism ; Homozygote ; Humans ; Infant, Newborn
Language	English
Publishing date	2022-01-26
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1141470-4
ISSN	1476-5438 ; 1018-4813
ISSN (online)	1476-5438
ISSN	1018-4813
DOI	10.1038/s41431-022-01043-8
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Zs.A 3589: Show issues

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Article ; Online: Single-cell protein expression of hiPSC-derived cardiomyocytes using Single-Cell Westerns.

Jabart, Eric / Molho, Josh / Sin, Kristina / Stansfield, Ben / Kazmouz, Sobhi G / Ventro, Daniela / Gardner, Kelly / Wu, Joseph C / Churko, Jared M

Journal of molecular and cellular cardiology

2020 Volume 149, Page(s) 115–122

Abstract: The ability to reprogram human somatic cells into human induced pluripotent stem cells (hiPSCs) has enabled researchers to generate cell types in vitro that have the potential to faithfully recapitulate patient-specific disease processes and phenotypes. ... ...

Abstract	The ability to reprogram human somatic cells into human induced pluripotent stem cells (hiPSCs) has enabled researchers to generate cell types in vitro that have the potential to faithfully recapitulate patient-specific disease processes and phenotypes. hiPSC-derived cardiomyocytes (hiPSC-CMs) offer the promise of in vitro patient- and disease-specific models for drug testing and the discovery of novel therapeutic approaches for treating cardiovascular diseases. While methods to differentiate hiPSCs into cardiomyocytes have been demonstrated, the heterogeneity and immaturity of these differentiated populations have restricted their potential in reproducing human disease and the associated target cell phenotypes. These barriers may be overcome through comprehensive single-cell characterization to dissect the rich heterogeneity of hiPSC-CMs and to study the source of varying cell fates. In this study, we optimized and validated a new Single-Cell Western method to assess protein expression in hiPSC-CMs. To better understand distinct subpopulations generated from cardiomyocyte differentiations and to track populations at single-cell resolution over time, we measured and quantified the expression of cardiomyocyte subtype-specific proteins (MLC2V and MLC2A) using Single-Cell Westerns. By understanding their heterogeneity through single-cell protein expression and quantification, we may improve upon current cardiomyocyte differentiation protocols, generate hiPSC-CMs that are more representative of in vivo derived cardiomyocytes for disease modeling, and utilize hiPSC-CMs for regenerative medicine purposes. Single-Cell Westerns provide a robust platform for protein expression analysis at single-cell resolution.
MeSH term(s)	Blotting, Western ; Calibration ; Cell Line ; Dietary Proteins/metabolism ; Humans ; Induced Pluripotent Stem Cells/cytology ; Induced Pluripotent Stem Cells/metabolism ; Myocytes, Cardiac/cytology ; Myocytes, Cardiac/metabolism ; Single-Cell Analysis
Chemical Substances	Dietary Proteins ; single cell proteins
Language	English
Publishing date	2020-10-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80157-4
ISSN	1095-8584 ; 0022-2828
ISSN (online)	1095-8584
ISSN	0022-2828
DOI	10.1016/j.yjmcc.2020.09.012
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Article ; Online: MMP inhibitors attenuate doxorubicin cardiotoxicity by preventing intracellular and extracellular matrix remodelling.

Chan, Brandon Y H / Roczkowsky, Andrej / Cho, Woo Jung / Poirier, Mathieu / Sergi, Consolato / Keschrumrus, Vic / Churko, Jared M / Granzier, Henk / Schulz, Richard

Cardiovascular research

2020 Volume 117, Issue 1, Page(s) 188–200

Abstract: Aims: Heart failure is a major complication in cancer treatment due to the cardiotoxic effects of anticancer drugs, especially from the anthracyclines such as doxorubicin (DXR). DXR enhances oxidative stress and stimulates matrix metalloproteinase-2 ( ... ...

Abstract	Aims: Heart failure is a major complication in cancer treatment due to the cardiotoxic effects of anticancer drugs, especially from the anthracyclines such as doxorubicin (DXR). DXR enhances oxidative stress and stimulates matrix metalloproteinase-2 (MMP-2) in cardiomyocytes. We investigated whether MMP inhibitors protect against DXR cardiotoxicity given the role of MMP-2 in proteolyzing sarcomeric proteins in the heart and remodelling the extracellular matrix. Methods and results: Eight-week-old male C57BL/6J mice were treated with DXR weekly with or without MMP inhibitors doxycycline or ONO-4817 by daily oral gavage for 4 weeks. Echocardiography was used to determine cardiac function and left ventricular remodelling before and after treatment. MMP inhibitors ameliorated DXR-induced systolic and diastolic dysfunction by reducing the loss in left ventricular ejection fraction, fractional shortening, and E'/A'. MMP inhibitors attenuated adverse left ventricular remodelling, reduced cardiomyocyte dropout, and prevented myocardial fibrosis. DXR increased myocardial MMP-2 activity in part also by upregulating N-terminal truncated MMP-2. Immunogold transmission electron microscopy showed that DXR elevated MMP-2 levels within the sarcomere and mitochondria which were associated with myofilament lysis, mitochondrial degeneration, and T-tubule distention. DXR-induced myofilament lysis was associated with increased titin proteolysis in the heart which was prevented by ONO-4817. DXR also increased the level and activity of MMP-2 in human embryonic stem cell-derived cardiomyocytes, which was reduced by ONO-4817. Conclusions: MMP-2 activation is an early event in DXR cardiotoxicity and contributes to myofilament lysis by proteolyzing cardiac titin. Two orally available MMP inhibitors ameliorated DXR cardiotoxicity by attenuating intracellular and extracellular matrix remodelling, suggesting their use may be a potential prophylactic strategy to prevent heart injury during chemotherapy.
MeSH term(s)	Animals ; Cardiotoxicity ; Cell Line ; Disease Models, Animal ; Doxorubicin ; Doxycycline/pharmacology ; Extracellular Matrix/drug effects ; Extracellular Matrix/enzymology ; Extracellular Matrix/pathology ; Fibrosis ; Heart Diseases/chemically induced ; Heart Diseases/enzymology ; Heart Diseases/physiopathology ; Heart Diseases/prevention & control ; Human Embryonic Stem Cells/drug effects ; Human Embryonic Stem Cells/enzymology ; Humans ; Male ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase Inhibitors/pharmacology ; Mice, Inbred C57BL ; Mitochondria, Heart/drug effects ; Mitochondria, Heart/enzymology ; Mitochondria, Heart/ultrastructure ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/enzymology ; Myocytes, Cardiac/ultrastructure ; Phenyl Ethers/pharmacology ; Protein Kinases/metabolism ; Proteolysis ; Ventricular Function, Left/drug effects ; Ventricular Remodeling/drug effects ; Mice
Chemical Substances	Matrix Metalloproteinase Inhibitors ; N-hydroxy-5-ethoxymethyloxy-2-methyl-4-(4-phenoxybenzoyl)aminopentanamide ; Phenyl Ethers ; Doxorubicin (80168379AG) ; Protein Kinases (EC 2.7.-) ; titin protein, mouse (EC 2.7.11.1) ; MMP2 protein, human (EC 3.4.24.24) ; Matrix Metalloproteinase 2 (EC 3.4.24.24) ; Mmp2 protein, mouse (EC 3.4.24.24) ; Doxycycline (N12000U13O)
Language	English
Publishing date	2020-01-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; 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/cvaa017
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