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  1. Article ; Online: Apelin regulates skeletal muscle adaptation to exercise in a high-intensity interval training model.

    Kilpiö, Teemu / Skarp, Sini / Perjés, Ábel / Swan, Julia / Kaikkonen, Leena / Saarimäki, Samu / Szokodi, István / Penninger, Josef M / Szabó, Zoltán / Magga, Johanna / Kerkelä, Risto

    American journal of physiology. Cell physiology

    2024  Volume 326, Issue 5, Page(s) C1437–C1450

    Abstract: Plasma apelin levels are reduced in aging and muscle wasting conditions. We aimed to investigate the significance of apelin signaling in cardiac and skeletal muscle responses to physiological stress. Apelin knockout (KO) and wild-type (WT) mice were ... ...

    Abstract Plasma apelin levels are reduced in aging and muscle wasting conditions. We aimed to investigate the significance of apelin signaling in cardiac and skeletal muscle responses to physiological stress. Apelin knockout (KO) and wild-type (WT) mice were subjected to high-intensity interval training (HIIT) by treadmill running. The effects of apelin on energy metabolism were studied in primary mouse skeletal muscle myotubes and cardiomyocytes. Apelin increased mitochondrial ATP production and mitochondrial coupling efficiency in myotubes and promoted the expression of mitochondrial genes both in primary myotubes and cardiomyocytes. HIIT induced mild concentric cardiac hypertrophy in WT mice, whereas eccentric growth was observed in the left ventricles of apelin KO mice. HIIT did not affect myofiber size in skeletal muscles of WT mice but decreased the myofiber size in apelin KO mice. The decrease in myofiber size resulted from a fiber type switch toward smaller slow-twitch type I fibers. The increased proportion of slow-twitch type I fibers in apelin KO mice was associated with upregulation of myosin heavy chain slow isoform expression, accompanied with upregulated expression of genes related to fatty acid transport and downregulated expression of genes related to glucose metabolism. Mechanistically, skeletal muscles of apelin KO mice showed defective induction of insulin-like growth factor-1 signaling in response to HIIT. In conclusion, apelin is required for proper skeletal and cardiac muscle adaptation to high-intensity exercise. Promoting apelinergic signaling may have benefits in aging- or disease-related muscle wasting conditions.
    MeSH term(s) Animals ; Apelin/metabolism ; Apelin/genetics ; Mice, Knockout ; Adaptation, Physiological ; Mice ; Physical Conditioning, Animal/physiology ; Muscle, Skeletal/metabolism ; High-Intensity Interval Training/methods ; Male ; Myocytes, Cardiac/metabolism ; Energy Metabolism ; Mice, Inbred C57BL ; Muscle Fibers, Skeletal/metabolism ; Muscle Fibers, Slow-Twitch/metabolism ; Cardiomegaly/metabolism ; Cardiomegaly/genetics ; Cardiomegaly/physiopathology ; Cardiomegaly/pathology
    Chemical Substances Apelin ; Apln protein, mouse
    Language English
    Publishing date 2024-03-25
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 392098-7
    ISSN 1522-1563 ; 0363-6143
    ISSN (online) 1522-1563
    ISSN 0363-6143
    DOI 10.1152/ajpcell.00427.2023
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. 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
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: MiR-185-5p regulates the development of myocardial fibrosis.

    Lin, Ruizhu / Rahtu-Korpela, Lea / Szabo, Zoltan / Kemppi, Anna / Skarp, Sini / Kiviniemi, Antti M / Lepojärvi, E Samuli / Halmetoja, Eveliina / Kilpiö, Teemu / Porvari, Katja / Pakanen, Lasse / Tolva, Johanna / Paakkanen, Riitta / Segersvärd, Heli / Tikkanen, Ilkka / Laine, Mika / Sinisalo, Juha / Lakkisto, Päivi / Huikuri, Heikki /
    Magga, Johanna / Junttila, Juhani / Kerkelä, Risto

    Journal of molecular and cellular cardiology

    2021  Volume 165, Page(s) 130–140

    Abstract: Background: Cardiac fibrosis stiffens the ventricular wall, predisposes to cardiac arrhythmias and contributes to the development of heart failure. In the present study, our aim was to identify novel miRNAs that regulate the development of cardiac ... ...

    Abstract Background: Cardiac fibrosis stiffens the ventricular wall, predisposes to cardiac arrhythmias and contributes to the development of heart failure. In the present study, our aim was to identify novel miRNAs that regulate the development of cardiac fibrosis and could serve as potential therapeutic targets for myocardial fibrosis.
    Methods and results: Analysis for cardiac samples from sudden cardiac death victims with extensive myocardial fibrosis as the primary cause of death identified dysregulation of miR-185-5p. Analysis of resident cardiac cells from mice subjected to experimental cardiac fibrosis model showed induction of miR-185-5p expression specifically in cardiac fibroblasts. In vitro, augmenting miR-185-5p induced collagen production and profibrotic activation in cardiac fibroblasts, whereas inhibition of miR-185-5p attenuated collagen production. In vivo, targeting miR-185-5p in mice abolished pressure overload induced cardiac interstitial fibrosis. Mechanistically, miR-185-5p targets apelin receptor and inhibits the anti-fibrotic effects of apelin. Finally, analysis of left ventricular tissue from patients with severe cardiomyopathy showed an increase in miR-185-5p expression together with pro-fibrotic TGF-β1 and collagen I.
    Conclusions: Our data show that miR-185-5p targets apelin receptor and promotes myocardial fibrosis.
    MeSH term(s) Animals ; Apelin Receptors/metabolism ; Cardiomyopathies/metabolism ; Collagen/metabolism ; Fibroblasts/metabolism ; Fibrosis ; Humans ; Mice ; MicroRNAs/metabolism
    Chemical Substances Apelin Receptors ; MIRN185 microRNA, human ; MicroRNAs ; Mirn185 microRNA, mouse ; Collagen (9007-34-5)
    Language English
    Publishing date 2021-12-29
    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.2021.12.011
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. 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
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Characterization of apela, a novel endogenous ligand of apelin receptor, in the adult heart.

    Perjés, Ábel / Kilpiö, Teemu / Ulvila, Johanna / Magga, Johanna / Alakoski, Tarja / Szabó, Zoltán / Vainio, Laura / Halmetoja, Eveliina / Vuolteenaho, Olli / Petäjä-Repo, Ulla / Szokodi, István / Kerkelä, Risto

    Basic research in cardiology

    2016  Volume 111, Issue 1, Page(s) 2

    Abstract: The G protein-coupled apelin receptor regulates important processes of the cardiovascular homeostasis, including cardiac development, cardiac contractility, and vascular tone. Most recently, a novel endogenous peptide ligand for the apelin receptor was ... ...

    Abstract The G protein-coupled apelin receptor regulates important processes of the cardiovascular homeostasis, including cardiac development, cardiac contractility, and vascular tone. Most recently, a novel endogenous peptide ligand for the apelin receptor was identified in zebrafish, and it was named apela/elabela/toddler. The peptide was originally considered as an exclusively embryonic regulator, and so far its function in the adult organism remains elusive. We show here that apela is predominantly expressed in the non-cardiomyocyte fraction in the adult rodent heart. We also provide evidence that apela binds to apelin receptors in the heart. Using isolated adult rat hearts, we demonstrate, that just like the fellow receptor agonist apelin, apela increases cardiac contractility and induces coronary vasodilation already in the nanomolar level. The inotropic effect, as revealed by Western blot analysis, is accompanied by a significant increase in extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. Pharmacological inhibition of ERK1/2 activation markedly attenuates the apela-induced inotropy. Analysis of samples from infarcted mouse hearts showed that expression of both apela and apelin receptor is induced in failing mouse hearts and correlate with left ventricular ejection fraction. Hence, we conclude that apela is present in the adult heart, is upregulated in post-infarction cardiac remodeling, and increases cardiac contractility in an ERK1/2-dependent manner.
    MeSH term(s) Aging ; Animals ; Apelin Receptors ; Blotting, Western ; Disease Models, Animal ; Heart ; Intercellular Signaling Peptides and Proteins/metabolism ; Male ; Mice ; Myocardial Infarction/metabolism ; Myocardium/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, G-Protein-Coupled/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/physiology
    Chemical Substances Apelin Receptors ; Aplnr protein, mouse ; Aplnr protein, rat ; Intercellular Signaling Peptides and Proteins ; Receptors, G-Protein-Coupled
    Language English
    Publishing date 2016-01
    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/s00395-015-0521-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: p38α regulates SERCA2a function.

    Kaikkonen, Leena / Magga, Johanna / Ronkainen, Veli-Pekka / Koivisto, Elina / Perjes, Ábel / Chuprun, J Kurt / Vinge, Leif Erik / Kilpiö, Teemu / Aro, Jani / Ulvila, Johanna / Alakoski, Tarja / Bibb, James A / Szokodi, Istvan / Koch, Walter J / Ruskoaho, Heikki / Kerkelä, Risto

    Journal of molecular and cellular cardiology

    2013  Volume 67, Page(s) 86–93

    Abstract: cAMP-dependent protein kinase (PKA) regulates the L-type calcium channel, the ryanodine receptor, and phospholamban (PLB) thereby increasing inotropy. Cardiac contractility is also regulated by p38 MAPK, which is a negative regulator of cardiac ... ...

    Abstract cAMP-dependent protein kinase (PKA) regulates the L-type calcium channel, the ryanodine receptor, and phospholamban (PLB) thereby increasing inotropy. Cardiac contractility is also regulated by p38 MAPK, which is a negative regulator of cardiac contractile function. The aim of this study was to identify the mechanism mediating the positive inotropic effect of p38 inhibition. Isolated adult and neonatal cardiomyocytes and perfused rat hearts were utilized to investigate the molecular mechanisms regulated by p38. PLB phosphorylation was enhanced in cardiomyocytes by chemical p38 inhibition, by overexpression of dominant negative p38α and by p38α RNAi, but not with dominant negative p38β. Treatment of cardiomyocytes with dominant negative p38α significantly decreased Ca(2+)-transient decay time indicating enhanced sarco/endoplasmic reticulum Ca(2+)-ATPase function and increased cardiomyocyte contractility. Analysis of signaling mechanisms involved showed that inhibition of p38 decreased the activity of protein phosphatase 2A, which renders protein phosphatase inhibitor-1 phosphorylated and thereby inhibits PP1. In conclusion, inhibition of p38α enhances PLB phosphorylation and diastolic Ca(2+) uptake. Our findings provide evidence for novel mechanism regulating cardiac contractility upon p38 inhibition.
    MeSH term(s) Animals ; Calcium/metabolism ; Calcium-Binding Proteins/metabolism ; Enzyme Activation/drug effects ; Muscle Contraction/physiology ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/physiology ; Phosphorylation ; RNA Interference ; Rats ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; p38 Mitogen-Activated Protein Kinases/pharmacology
    Chemical Substances Calcium-Binding Proteins ; phospholamban ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Sarcoplasmic Reticulum Calcium-Transporting ATPases (EC 3.6.3.8) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2013-12-17
    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.2013.12.005
    Database MEDical Literature Analysis and Retrieval System OnLINE

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