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ACVR2B

The Experts below are selected from a list of 954 Experts worldwide ranked by ideXlab platform

Juha J. Hulmi – 1st expert on this subject based on the ideXlab platform

  • systemic blockade of ACVR2B ligands attenuates muscle wasting in ischemic heart failure without compromising cardiac function
    The FASEB Journal, 2020
    Co-Authors: Zoltan Szabo, Juha J. Hulmi, Arja Pasternack, Laura Vainio, Lea Rahtukorpela, Julia Swan, Raisa Serpi, Mika Laitinen, Olli Ritvos

    Abstract:

    : Signaling through activin receptors regulates skeletal muscle mass and activin receptor 2B (ACVR2B) ligands are also suggested to participate in myocardial infarction (MI) pathology in the heart. In this study, we determined the effect of systemic blockade of ACVR2B ligands on cardiac function in experimental MI, and defined its efficacy to revert muscle wasting in ischemic heart failure (HF). Mice were treated with soluble ACVR2B decoy receptor (ACVR2B-Fc) to study its effect on post-MI cardiac remodeling and on later HF. Cardiac function was determined with echocardiography, and myocardium analyzed with histological and biochemical methods for hypertrophy and fibrosis. Pharmacological blockade of ACVR2B ligands did not rescue the heart from ischemic injury or alleviate post-MI remodeling and ischemic HF. Collectively, ACVR2B-Fc did not affect cardiomyocyte hypertrophy, fibrosis, angiogenesis, nor factors associated with cardiac regeneration except modification of certain genes involved in metabolism or cell growth/survival. ACVR2B-Fc, however, was able to reduce skeletal muscle wasting in chronic ischemic HF, accompanied by reduced LC3II as a marker of autophagy and increased mTOR signaling and Cited4 expression as markers of physiological hypertrophy in quadriceps muscle. Our results ascertain pharmacological blockade of ACVR2B ligands as a possible therapy for skeletal muscle wasting in ischemic HF. Pharmacological blockade of ACVR2B ligands preserved myofiber size in ischemic HF, but did not compromise cardiac function nor exacerbate cardiac remodeling after ischemic injury.

  • Muscle and serum metabolomes are dysregulated in colon-26 tumor-bearing mice despite amelioration of cachexia with activin receptor type 2B ligand blockade.
    American Journal of Physiology-endocrinology and Metabolism, 2019
    Co-Authors: Juulia H Lautaoja, Jaakko Hentilä, Olli Ritvos, Tuuli A Nissinen, Maciej Lalowski, Sulin Cheng, Juha J. Hulmi

    Abstract:

    Cancer-associated cachexia reduces survival, which has been attenuated by blocking the activin receptor type 2B (ACVR2B) ligands in mice. The purpose of this study was to unravel the underlying phy…

  • systemic blockade of ACVR2B ligands protects myocardium from acute ischemia reperfusion injury
    Molecular Therapy, 2019
    Co-Authors: Johanna Magga, Juha J. Hulmi, Markus Rasanen, Laura Vainio, Teemu Kilpio, Saija Taponen, Zoltan Szabo, Lea Rahtukorpela, Tarja Alakoski

    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.

Toril Holien – 2nd expert on this subject based on the ideXlab platform

  • BMPR2 inhibits activin and BMP signaling via wild-type ALK2.
    Journal of Cell Science, 2018
    Co-Authors: Oddrun Elise Olsen, Hanne Hella, Meenu Sankar, Samah Elsaadi, Glenn Buene, Sagar Ramesh Darvekar, Kristine Misund, Takenobu Katagiri, Petra Knaus, Toril Holien

    Abstract:

    TGF-β/BMP superfamily ligands require heteromeric complexes of type 1 and 2 receptors for ligand dependent downstream signaling. Activin A, a TGF-β superfamily member, inhibits growth of multiple myeloma cells, but the mechanism is unknown. We aimed to clarify how activins affect myeloma cell survival. Activin A activates the transcription factors SMAD2/3 through the ALK4 type 1 receptor, but may also activate SMAD1/5/8 through mutated variants of the type 1 receptor ALK2. We demonstrate that activin A and B activate SMAD1/5/8 in myeloma cells through endogenous wild type ALK2. Knockdown of the type 2 receptor BMPR2 strongly potentiated activin A- and B-induced SMAD1/5/8 activation and subsequent cell death. Furthermore, activity of BMP6, BMP7 or BMP9, which also may signal via ALK2, was potentiated by BMPR2 knockdown. Similar results were seen in HepG2 liver carcinoma cells. We propose that BMPR2 inhibits ALK2-mediated signaling by preventing ALK2 from oligomerizing with the type 2 receptors ACVR2A and ACVR2B, necessary for ALK2 activation by activins and several BMPs. In conclusion, BMPR2 could be explored as a possible target for therapy in patients with multiple myeloma.

  • BMPR2 inhibits activin- and BMP-signaling via wild type ALK2
    bioRxiv, 2017
    Co-Authors: Oddrun Elise Olsen, Hanne Hella, Meenu Sankar, Samah Elsaadi, Glenn Buene, Sagar Ramesh Darvekar, Kristine Misund, Takenobu Katagiri, Toril Holien

    Abstract:

    Activin A is a member of the TGF-β superfamily and activates the transcription factors SMAD2/3 through the ALK4 type 1 receptor. Activin A has also been shown to activate SMAD1/5/8 through mutated variants of the type 1 receptor ALK2. Interestingly, we here show that both activin A and activin B could activate SMAD1/5/8 through endogenous wild type ALK2 in multiple myeloma cells. Knockdown of the type 2 receptor BMPR2 strongly potentiated activin A- and activin B-induced SMAD1/5/8 activation and subsequent cell death. Furthermore, activity of BMP6, BMP7 or BMP9, which also signal via ALK2, was potentiated by BMPR2 knockdown. Similar results were seen in HepG2 liver carcinoma cells. We propose that BMPR2 inhibited ALK2-mediated signaling by preventing ALK2 from oligomerizing with the type 2 receptors ACVR2A and ACVR2B, necessary for ALK2 activation by activins and several BMPs in these cells. In conclusion, BMPR2 could be explored as a possible target for therapy in patients with multiple myeloma.

  • activin a inhibits bmp signaling by binding acvr2a and ACVR2B
    Cell Communication and Signaling, 2015
    Co-Authors: Oddrun Elise Olsen, Karin Fahl Wader, Hanne Hella, Anne K Mylin, Ingemar Turesson, Ingerid Nesthus, Anders Waage, Anders Sundan, Toril Holien

    Abstract:

    Background: Activins are members of the TGF-β family of ligands that have multiple biological functions in embryonic stem cells as well as in differentiated tissue. Serum levels of activin A were found to be elevated in pathological conditions such as cachexia, osteoporosis and cancer. Signaling by activin A through canonical ALK4-ACVR2 receptor complexes activates the transcription factors SMAD2 and SMAD3. Activin A has a strong affinity to type 2 receptors, a feature that they share with some of the bone morphogenetic proteins (BMPs). Activin A is also elevated in myeloma patients with advanced disease and is involved in myeloma bone disease. Results: In this study we investigated effects of activin A binding to receptors that are shared with BMPs using myeloma cell lines with well-characterized BMP-receptor expression and responses. Activin A antagonized BMP-6 and BMP-9, but not BMP-2 and BMP-4. Activin A was able to counteract BMPs that signal through the type 2 receptors ACVR2A and ACVR2B in combination with ALK2, but not BMPs that signal through BMPR2 in combination with ALK3 and ALK6. Conclusions: We propose that one important way that activin A regulates cell behavior is by antagonizing BMP-ACVR2A/ACVR2B/ALK2 signaling.

Oddrun Elise Olsen – 3rd expert on this subject based on the ideXlab platform

  • BMPR2 inhibits activin and BMP signaling via wild-type ALK2.
    Journal of Cell Science, 2018
    Co-Authors: Oddrun Elise Olsen, Hanne Hella, Meenu Sankar, Samah Elsaadi, Glenn Buene, Sagar Ramesh Darvekar, Kristine Misund, Takenobu Katagiri, Petra Knaus, Toril Holien

    Abstract:

    TGF-β/BMP superfamily ligands require heteromeric complexes of type 1 and 2 receptors for ligand dependent downstream signaling. Activin A, a TGF-β superfamily member, inhibits growth of multiple myeloma cells, but the mechanism is unknown. We aimed to clarify how activins affect myeloma cell survival. Activin A activates the transcription factors SMAD2/3 through the ALK4 type 1 receptor, but may also activate SMAD1/5/8 through mutated variants of the type 1 receptor ALK2. We demonstrate that activin A and B activate SMAD1/5/8 in myeloma cells through endogenous wild type ALK2. Knockdown of the type 2 receptor BMPR2 strongly potentiated activin A- and B-induced SMAD1/5/8 activation and subsequent cell death. Furthermore, activity of BMP6, BMP7 or BMP9, which also may signal via ALK2, was potentiated by BMPR2 knockdown. Similar results were seen in HepG2 liver carcinoma cells. We propose that BMPR2 inhibits ALK2-mediated signaling by preventing ALK2 from oligomerizing with the type 2 receptors ACVR2A and ACVR2B, necessary for ALK2 activation by activins and several BMPs. In conclusion, BMPR2 could be explored as a possible target for therapy in patients with multiple myeloma.

  • BMPR2 inhibits activin- and BMP-signaling via wild type ALK2
    bioRxiv, 2017
    Co-Authors: Oddrun Elise Olsen, Hanne Hella, Meenu Sankar, Samah Elsaadi, Glenn Buene, Sagar Ramesh Darvekar, Kristine Misund, Takenobu Katagiri, Toril Holien

    Abstract:

    Activin A is a member of the TGF-β superfamily and activates the transcription factors SMAD2/3 through the ALK4 type 1 receptor. Activin A has also been shown to activate SMAD1/5/8 through mutated variants of the type 1 receptor ALK2. Interestingly, we here show that both activin A and activin B could activate SMAD1/5/8 through endogenous wild type ALK2 in multiple myeloma cells. Knockdown of the type 2 receptor BMPR2 strongly potentiated activin A- and activin B-induced SMAD1/5/8 activation and subsequent cell death. Furthermore, activity of BMP6, BMP7 or BMP9, which also signal via ALK2, was potentiated by BMPR2 knockdown. Similar results were seen in HepG2 liver carcinoma cells. We propose that BMPR2 inhibited ALK2-mediated signaling by preventing ALK2 from oligomerizing with the type 2 receptors ACVR2A and ACVR2B, necessary for ALK2 activation by activins and several BMPs in these cells. In conclusion, BMPR2 could be explored as a possible target for therapy in patients with multiple myeloma.

  • activin a inhibits bmp signaling by binding acvr2a and ACVR2B
    Cell Communication and Signaling, 2015
    Co-Authors: Oddrun Elise Olsen, Karin Fahl Wader, Hanne Hella, Anne K Mylin, Ingemar Turesson, Ingerid Nesthus, Anders Waage, Anders Sundan, Toril Holien

    Abstract:

    Background: Activins are members of the TGF-β family of ligands that have multiple biological functions in embryonic stem cells as well as in differentiated tissue. Serum levels of activin A were found to be elevated in pathological conditions such as cachexia, osteoporosis and cancer. Signaling by activin A through canonical ALK4-ACVR2 receptor complexes activates the transcription factors SMAD2 and SMAD3. Activin A has a strong affinity to type 2 receptors, a feature that they share with some of the bone morphogenetic proteins (BMPs). Activin A is also elevated in myeloma patients with advanced disease and is involved in myeloma bone disease. Results: In this study we investigated effects of activin A binding to receptors that are shared with BMPs using myeloma cell lines with well-characterized BMP-receptor expression and responses. Activin A antagonized BMP-6 and BMP-9, but not BMP-2 and BMP-4. Activin A was able to counteract BMPs that signal through the type 2 receptors ACVR2A and ACVR2B in combination with ALK2, but not BMPs that signal through BMPR2 in combination with ALK3 and ALK6. Conclusions: We propose that one important way that activin A regulates cell behavior is by antagonizing BMP-ACVR2A/ACVR2B/ALK2 signaling.