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Article ; Online: RNA silencing in the antiviral innate immune defence--role of DEAD-box RNA helicases.

Ulvila, J / Hultmark, D / Rämet, M

2010 Volume 71, Issue 3, Page(s) 146–158

Abstract: RNA silencing is an efficient biochemical tool for gene knock downs as well as physiological phenomenon playing a major role in diverse biological processes. Recent knowledge suggests that the same protein families which mediate the experimental RNA ... ...

Abstract	RNA silencing is an efficient biochemical tool for gene knock downs as well as physiological phenomenon playing a major role in diverse biological processes. Recent knowledge suggests that the same protein families which mediate the experimental RNA interference (RNAi) in the fruit fly Drosophila melanogaster cells also contribute to the antiviral host defence in both invertebrate model organisms and mammals. Additionally, another branch of RNA silencing, the microRNAs (miRNAs), has been recently described in the context of host defence. In several studies, miRNAs have been shown to regulate essential immune responses. This review summarizes basic concepts of RNAi and miRNAs, especially in the context of immune defence, focusing on the newly discovered role of DEAD-box helicases in the RNA interference and antiviral host defence.
MeSH term(s)	Animals ; DEAD-box RNA Helicases/immunology ; Drosophila melanogaster/immunology ; Humans ; Immunity, Innate/immunology ; Mice ; MicroRNAs/immunology ; RNA Interference/immunology ; RNA, Small Interfering/immunology ; Virus Diseases/enzymology ; Virus Diseases/immunology
Chemical Substances	MicroRNAs ; RNA, Small Interfering ; DEAD-box RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2010-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	120476-2
ISSN	1365-3083 ; 0300-9475
ISSN (online)	1365-3083
ISSN	0300-9475
DOI	10.1111/j.1365-3083.2009.02362.x
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Article: RNA Silencing in the Antiviral Innate Immune Defence - Role of DEAD-box RNA Helicases

Ulvila, J / Hultmark, D / Rämet, M

Scandinavian journal of immunology. 2010 Mar., v. 71, no. 3

2010

Abstract	RNA silencing is an efficient biochemical tool for gene knock downs as well as physiological phenomenon playing a major role in diverse biological processes. Recent knowledge suggests that the same protein families which mediate the experimental RNA interference (RNAi) in the fruit fly Drosophila melanogaster cells also contribute to the antiviral host defence in both invertebrate model organisms and mammals. Additionally, another branch of RNA silencing, the microRNAs (miRNAs), has been recently described in the context of host defence. In several studies, miRNAs have been shown to regulate essential immune responses. This review summarizes basic concepts of RNAi and miRNAs, especially in the context of immune defence, focusing on the newly discovered role of DEAD-box helicases in the RNA interference and antiviral host defence.
Language	English
Dates of publication	2010-03
Size	p. 146-158.
Publisher	Blackwell Publishing Ltd
Publishing place	Oxford, UK
Document type	Article
ZDB-ID	120476-2
ISSN	1365-3083 ; 0300-9475
ISSN (online)	1365-3083
ISSN	0300-9475
DOI	10.1111/j.1365-3083.2009.02362.x
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Article ; Online: Natriuretic Peptides in the Regulation of Cardiovascular Physiology and Metabolic Events.

Kerkelä, Risto / Ulvila, Johanna / Magga, Johanna

Journal of the American Heart Association

2015 Volume 4, Issue 10, Page(s) e002423

MeSH term(s)	Animals ; Diabetes Mellitus/metabolism ; Energy Metabolism/drug effects ; Gene Expression Regulation ; Heart Diseases/drug therapy ; Heart Diseases/genetics ; Heart Diseases/metabolism ; Heart Diseases/pathology ; Heart Diseases/physiopathology ; Humans ; Metabolic Syndrome/metabolism ; Myocardium/metabolism ; Myocardium/pathology ; Natriuretic Peptides/genetics ; Natriuretic Peptides/metabolism ; Natriuretic Peptides/therapeutic use ; Receptors, Atrial Natriuretic Factor/metabolism ; Signal Transduction/drug effects
Chemical Substances	Natriuretic Peptides ; Receptors, Atrial Natriuretic Factor (EC 4.6.1.2)
Language	English
Publishing date	2015-10-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2653953-6
ISSN	2047-9980 ; 2047-9980
ISSN (online)	2047-9980
ISSN	2047-9980
DOI	10.1161/JAHA.115.002423
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Article ; Online: Inhibition of cardiomyocyte Sprouty1 protects from cardiac ischemia-reperfusion injury.

Alakoski, Tarja / Ulvila, Johanna / Yrjölä, Raisa / Vainio, Laura / Magga, Johanna / Szabo, Zoltan / Licht, Jonathan D / Kerkelä, Risto

Basic research in cardiology

2019 Volume 114, Issue 2, Page(s) 7

Abstract: Sprouty1 (Spry1) is a negative modulator of receptor tyrosine kinase signaling, but its role in cardiomyocyte survival has not been elucidated. The aim of this study was to investigate the potential role of cardiomyocyte Spry1 in cardiac ischemia- ... ...

Abstract	Sprouty1 (Spry1) is a negative modulator of receptor tyrosine kinase signaling, but its role in cardiomyocyte survival has not been elucidated. The aim of this study was to investigate the potential role of cardiomyocyte Spry1 in cardiac ischemia-reperfusion (I/R) injury. Infarct areas of mouse hearts showed an increase in Spry1 protein expression, which localized to cardiomyocytes. To investigate if cardiomyocyte Spry1 regulates I/R injury, 8-week-old inducible cardiomyocyte Spry1 knockout (Spry1 cKO) mice and control mice were subjected to cardiac I/R injury. Spry1 cKO mice showed reduction in release of cardiac troponin I and reduced infarct size after I/R injury compared to control mice. Similar to Spry1 knockdown in cardiomyocytes in vivo, RNAi-mediated Spry1 silencing in isolated cardiomyocytes improved cardiomyocyte survival following simulated ischemia injury. Mechanistically, Spry1 knockdown induced cardiomyocyte extracellular signal-regulated kinase (ERK) phosphorylation in healthy hearts and isolated cardiomyocytes, and enhanced ERK phosphorylation after I/R injury. Spry1-deficient cardiomyocytes showed better preserved mitochondrial membrane potential following ischemic injury and an increase in levels of phosphorylated ERK and phosphorylated glycogen synthase kinase-3β (GSK-3β) in mitochondria of hypoxic cardiomyocytes. Overexpression of constitutively active GSK-3β abrogated the protective effect of Spry1 knockdown. Moreover, pharmacological inhibition of GSK-3β protected wild-type cardiomyocytes from cell death, but did not further protect Spry1-silenced cardiomyocytes from hypoxia-induced injury. Cardiomyocyte Spry1 knockdown promotes ERK phosphorylation and offers protection from I/R injury. Our findings indicate that Spry1 is an important regulator of cardiomyocyte viability during ischemia-reperfusion injury.
MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Cell Survival/physiology ; Male ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myocardial Reperfusion Injury/metabolism ; Myocytes, Cardiac/metabolism ; Phosphoproteins/metabolism ; Rats
Chemical Substances	Adaptor Proteins, Signal Transducing ; Membrane Proteins ; Phosphoproteins ; Spry1 protein, mouse
Language	English
Publishing date	2019-01-11
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	189755-x
ISSN	1435-1803 ; 0300-8428 ; 0175-9418
ISSN (online)	1435-1803
ISSN	0300-8428 ; 0175-9418
DOI	10.1007/s00395-018-0713-y
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Article ; Online: GSK3β Serine 389 Phosphorylation Modulates Cardiomyocyte Hypertrophy and Ischemic Injury.

Vainio, Laura / Taponen, Saija / Kinnunen, Sini M / Halmetoja, Eveliina / Szabo, Zoltan / Alakoski, Tarja / Ulvila, Johanna / Junttila, Juhani / Lakkisto, Päivi / Magga, Johanna / Kerkelä, Risto

International journal of molecular sciences

2021 Volume 22, Issue 24

Abstract: Prior studies show that glycogen synthase kinase 3β (GSK3β) contributes to cardiac ischemic injury and cardiac hypertrophy. GSK3β is constitutionally active and phosphorylation of GSK3β at serine 9 (S9) inactivates the kinase and promotes cellular growth. ...

Abstract	Prior studies show that glycogen synthase kinase 3β (GSK3β) contributes to cardiac ischemic injury and cardiac hypertrophy. GSK3β is constitutionally active and phosphorylation of GSK3β at serine 9 (S9) inactivates the kinase and promotes cellular growth. GSK3β is also phosphorylated at serine 389 (S389), but the significance of this phosphorylation in the heart is not known. We analyzed GSK3β S389 phosphorylation in diseased hearts and utilized overexpression of GSK3β carrying ser→ala mutations at S9 (S9A) and S389 (S389A) to study the biological function of constitutively active GSK3β in primary cardiomyocytes. We found that phosphorylation of GSK3β at S389 was increased in left ventricular samples from patients with dilated cardiomyopathy and ischemic cardiomyopathy, and in hearts of mice subjected to thoracic aortic constriction. Overexpression of either GSK3β S9A or S389A reduced the viability of cardiomyocytes subjected to hypoxia-reoxygenation. Overexpression of double GSK3β mutant (S9A/S389A) further reduced cardiomyocyte viability. Determination of protein synthesis showed that overexpression of GSK3β S389A or GSK3β S9A/S389A increased both basal and agonist-induced cardiomyocyte growth. Mechanistically, GSK3β S389A mutation was associated with activation of mTOR complex 1 signaling. In conclusion, our data suggest that phosphorylation of GSK3β at S389 enhances cardiomyocyte survival and protects from cardiomyocyte hypertrophy.
MeSH term(s)	Animals ; Cardiomegaly/metabolism ; Cardiomegaly/pathology ; Cell Proliferation ; Cell Survival ; Cells, Cultured ; Glycogen Synthase Kinase 3 beta/metabolism ; Humans ; Male ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Mice ; Mice, Inbred C57BL ; Myocardial Ischemia/metabolism ; Myocardial Ischemia/pathology ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Phosphorylation ; Rats, Sprague-Dawley ; Rats
Chemical Substances	GSK3B protein, human (EC 2.7.11.1) ; Glycogen Synthase Kinase 3 beta (EC 2.7.11.1) ; Gsk3b protein, mouse (EC 2.7.11.1) ; Gsk3b protein, rat (EC 2.7.11.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1)
Language	English
Publishing date	2021-12-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms222413586
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Article: miR-1468-3p Promotes Aging-Related Cardiac Fibrosis.

Lin, Ruizhu / Rahtu-Korpela, Lea / Magga, Johanna / Ulvila, Johanna / Swan, Julia / Kemppi, Anna / Pakanen, Lasse / Porvari, Katja / Huikuri, Heikki / Junttila, Juhani / Kerkelä, Risto

Molecular therapy. Nucleic acids

2020 Volume 20, Page(s) 589–605

Abstract: Non-coding microRNAs (miRNAs) are powerful regulators of gene expression and critically involved in cardiovascular pathophysiology. The aim of the current study was to identify miRNAs regulating cardiac fibrosis. Cardiac samples of age-matched control ... ...

Abstract	Non-coding microRNAs (miRNAs) are powerful regulators of gene expression and critically involved in cardiovascular pathophysiology. The aim of the current study was to identify miRNAs regulating cardiac fibrosis. Cardiac samples of age-matched control subjects and sudden cardiac death (SCD) victims with primary myocardial fibrosis (PMF) were subjected to miRNA profiling. Old SCD victims with PMF and healthy aged human hearts showed increased expression of miR-1468-3p. In vitro studies in human cardiac fibroblasts showed that augmenting miR-1468-3p levels induces collagen deposition and cell metabolic activity and enhances collagen 1, connective tissue growth factor, and periostin expression. In addition, miR-1468-3p promotes cellular senescence with increased senescence-associated β-galactosidase activity and increased expression of p53 and p16. AntimiR-1468-3p antagonized transforming growth factor β1 (TGF-β1)-induced collagen deposition and metabolic activity. Mechanistically, mimic-1468-3p enhanced p38 phosphorylation, while antimiR-1468-3p decreased TGF-β1-induced p38 activation and abolished p38-induced collagen deposition. RNA sequencing analysis, a computational prediction model, and qPCR analysis identified dual-specificity phosphatases (DUSPs) as miR-1468-3p target genes, and regulation of DUSP1 by miR-1468-3p was confirmed with a dual-luciferase reporter assay. In conclusion, miR-1468-3p promotes cardiac fibrosis by enhancing TGF-β1-p38 signaling. Targeting miR-1468-3p in the older population may be of therapeutic interest to reduce cardiac fibrosis.
Language	English
Publishing date	2020-04-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2662631-7
ISSN	2162-2531
ISSN	2162-2531
DOI	10.1016/j.omtn.2020.04.001
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Article ; Online: Drosophila phagocytosis - still many unknowns under the surface.

Ulvila, Johanna / Vanha-Aho, Leena-Maija / Rämet, Mika

APMIS : acta pathologica, microbiologica, et immunologica Scandinavica

2011 Volume 119, Issue 10, Page(s) 651–662

Abstract: In mammals, phagocytosis coordinates host defence on two levels: It acts both as an effector of the innate immunity, as well as an initiator of the adaptive immunity. The fruit fly Drosophila melanogaster (D. melanogaster) lacks the adaptive immune ... ...

Abstract	In mammals, phagocytosis coordinates host defence on two levels: It acts both as an effector of the innate immunity, as well as an initiator of the adaptive immunity. The fruit fly Drosophila melanogaster (D. melanogaster) lacks the adaptive immune response, and the role of Drosophila plasmatocytes, cells that resemble phagocytosing mammalian macrophages, is limited to innate immune responses. During the past years, several studies have shed light on the role of phagocytosis in the Drosophila host defence. At least in some infection models, the systemic production of potent antimicrobial peptides (AMPs) does not completely compensate for the need for cellular immune responses. As a model, Drosophila offers powerful tools for studying phagocytosis including, large-scale RNA interference (RNAi) based in vitro screens that can be combined with classical Drosophila genetics. These kinds of approaches have led to important discoveries related especially to microbial recognition by Drosophila plasmatocytes. Events following initial recognition, however, have remained more elusive. This review summarizes the current knowledge on Drosophila phagocytosis focusing on the most recent advancements in the field, and highlighting the benefits the Drosophila system has to offer for research on phagocytosis.
MeSH term(s)	Animals ; Drosophila melanogaster/cytology ; Drosophila melanogaster/genetics ; Drosophila melanogaster/immunology ; Hemocytes/immunology ; Host-Pathogen Interactions/immunology ; Immunity, Innate/immunology ; Phagocytosis/genetics ; Phagocytosis/immunology ; Signal Transduction/immunology
Language	English
Publishing date	2011-10
Publishing country	Denmark
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	93340-5
ISSN	1600-0463 ; 0903-4641
ISSN (online)	1600-0463
ISSN	0903-4641
DOI	10.1111/j.1600-0463.2011.02792.x
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Article ; Online: Vezf1 regulates cardiac structure and contractile function.

Paavola, Jere / Alakoski, Tarja / Ulvila, Johanna / Kilpiö, Teemu / Sirén, Juuso / Perttunen, Sanni / Narumanchi, Suneeta / Wang, Hong / Lin, Ruizhu / Porvari, Katja / Junttila, Juhani / Huikuri, Heikki / Immonen, Katariina / Lakkisto, Päivi / Magga, Johanna / Tikkanen, Ilkka / Kerkelä, Risto

EBioMedicine

2020 Volume 51, Page(s) 102608

Abstract: Background: Vascular endothelial zinc finger 1 (Vezf1) is a transcription factor previously shown to regulate vasculogenesis and angiogenesis. We aimed to investigate the role of Vezf1 in the postnatal heart.: Methods: The role of Vezf1 in regulating ...

Abstract	Background: Vascular endothelial zinc finger 1 (Vezf1) is a transcription factor previously shown to regulate vasculogenesis and angiogenesis. We aimed to investigate the role of Vezf1 in the postnatal heart. Methods: The role of Vezf1 in regulating cardiac growth and contractile function was studied in zebrafish and in primary cardiomyocytes. Findings: We find that expression of Vezf1 is decreased in diseased human myocardium and mouse hearts. Our experimental data shows that knockdown of zebrafish Vezf1 reduces cardiac growth and results in impaired ventricular contractile response to β-adrenergic stimuli. However, Vezf1 knockdown is not associated with dysregulation of cardiomyocyte Ca Interpretation: We demonstrate a role for Vezf1 in regulation of compensatory cardiac growth and cardiomyocyte contractile function, which may be relevant in human cardiac disease.
MeSH term(s)	Adrenergic Agents/pharmacology ; Animals ; Binding Sites ; Cardiomyopathies/genetics ; DNA-Binding Proteins/metabolism ; Gene Expression Regulation/drug effects ; Genes, Reporter ; Humans ; Luciferases/metabolism ; Mice, Inbred C57BL ; Myocardial Contraction ; Myocardium/metabolism ; Myocardium/pathology ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; Myosin Heavy Chains/genetics ; Myosin Heavy Chains/metabolism ; Neovascularization, Physiologic/drug effects ; Promoter Regions, Genetic/genetics ; Protein Binding/drug effects ; Rats, Sprague-Dawley ; Transcription Factors/metabolism ; Zebrafish ; Zebrafish Proteins/metabolism
Chemical Substances	Adrenergic Agents ; DNA-Binding Proteins ; Transcription Factors ; VEZF1 protein, human ; Vezf1 protein, mouse ; Zebrafish Proteins ; vezf1b protein, zebrafish ; Luciferases (EC 1.13.12.-) ; Myosin Heavy Chains (EC 3.6.4.1)
Language	English
Publishing date	2020-01-03
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2019.102608
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Article ; Online: Connective Tissue Growth Factor Inhibition Enhances Cardiac Repair and Limits Fibrosis After Myocardial Infarction.

Vainio, Laura E / Szabó, Zoltán / Lin, Ruizhu / Ulvila, Johanna / Yrjölä, Raisa / Alakoski, Tarja / Piuhola, Jarkko / Koch, Walter J / Ruskoaho, Heikki / Fouse, Shaun D / Seeley, Todd W / Gao, Erhe / Signore, Pierre / Lipson, Kenneth E / Magga, Johanna / Kerkelä, Risto

JACC. Basic to translational science

2019 Volume 4, Issue 1, Page(s) 83–94

Abstract: Myocardial infarction (MI)-induced cardiac fibrosis attenuates cardiac contractile function, and predisposes to arrhythmias and sudden cardiac death. Expression of connective tissue growth factor (CTGF) is elevated in affected organs in virtually every ... ...

Abstract	Myocardial infarction (MI)-induced cardiac fibrosis attenuates cardiac contractile function, and predisposes to arrhythmias and sudden cardiac death. Expression of connective tissue growth factor (CTGF) is elevated in affected organs in virtually every fibrotic disorder and in the diseased human myocardium. Mice were subjected to treatment with a CTGF monoclonal antibody (mAb) during infarct repair, post-MI left ventricular (LV) remodeling, or acute ischemia-reperfusion injury. CTGF mAb therapy during infarct repair improved survival and reduced LV dysfunction, and reduced post-MI LV hypertrophy and fibrosis. Mechanistically, CTGF mAb therapy induced expression of cardiac developmental and/or repair genes and attenuated expression of inflammatory and/or fibrotic genes.
Language	English
Publishing date	2019-02-25
Publishing country	United States
Document type	Journal Article
ISSN	2452-302X
ISSN (online)	2452-302X
DOI	10.1016/j.jacbts.2018.10.007
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Article ; Online: Systemic Blockade of ACVR2B Ligands Protects Myocardium from Acute Ischemia-Reperfusion Injury.

Magga, Johanna / Vainio, Laura / Kilpiö, Teemu / Hulmi, Juha J / Taponen, Saija / Lin, Ruizhu / Räsänen, Markus / Szabó, Zoltán / Gao, Erhe / Rahtu-Korpela, Lea / Alakoski, Tarja / Ulvila, Johanna / Laitinen, Mika / Pasternack, Arja / Koch, Walter J / Alitalo, Kari / Kivelä, Riikka / Ritvos, Olli / Kerkelä, Risto

Molecular therapy : the journal of the American Society of Gene Therapy

2019 Volume 27, Issue 3, Page(s) 600–610

Abstract: Activin A and myostatin, members of the transforming growth factor (TGF)-β superfamily of secreted factors, are potent negative regulators of muscle growth, but their contribution to myocardial ischemia-reperfusion (IR) injury is not known. The aim of ... ...

Abstract	Activin A and myostatin, members of the transforming growth factor (TGF)-β superfamily of secreted factors, are potent negative regulators of muscle growth, but their contribution to myocardial ischemia-reperfusion (IR) injury is not known. The aim of this study was to investigate if activin 2B (ACVR2B) receptor ligands contribute to myocardial IR injury. Mice were treated with soluble ACVR2B decoy receptor (ACVR2B-Fc) and subjected to myocardial ischemia followed by reperfusion for 6 or 24 h. Systemic blockade of ACVR2B ligands by ACVR2B-Fc was protective against cardiac IR injury, as evidenced by reduced infarcted area, apoptosis, and autophagy and better preserved LV systolic function following IR. ACVR2B-Fc modified cardiac metabolism, LV mitochondrial respiration, as well as cardiac phenotype toward physiological hypertrophy. Similar to its protective role in IR injury in vivo, ACVR2B-Fc antagonized SMAD2 signaling and cell death in cardiomyocytes that were subjected to hypoxic stress. ACVR2B ligand myostatin was found to exacerbate hypoxic stress. In addition to acute cardioprotection in ischemia, ACVR2B-Fc provided beneficial effects on cardiac function in prolonged cardiac stress in cardiotoxicity model. By blocking myostatin, ACVR2B-Fc potentially reduces cardiomyocyte death and modifies cardiomyocyte metabolism for hypoxic conditions to protect the heart from IR injury.
MeSH term(s)	Activin Receptors, Type II/genetics ; Activin Receptors, Type II/metabolism ; Animals ; Male ; Mice ; Mice, Inbred C57BL ; Myocardial Reperfusion Injury/metabolism ; Myocardium/metabolism ; Myocytes, Cardiac/metabolism ; Myostatin/metabolism ; Signal Transduction/genetics ; Signal Transduction/physiology ; Smad2 Protein/genetics ; Smad2 Protein/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	Cited4 protein, mouse ; Myostatin ; Smad2 Protein ; Transcription Factors ; Activin Receptors, Type II (EC 2.7.11.30) ; activin receptor type II-B (EC 2.7.11.30)
Language	English
Publishing date	2019-01-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2010592-7
ISSN	1525-0024 ; 1525-0016
ISSN (online)	1525-0024
ISSN	1525-0016
DOI	10.1016/j.ymthe.2019.01.013
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