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  1. Article ; Online: The road toward microRNA therapeutics.

    Seto, Anita G

    The international journal of biochemistry & cell biology

    2010  Volume 42, Issue 8, Page(s) 1298–1305

    Abstract: Within the last 15 years, microRNAs (miRNAs) have emerged as powerful regulators of gene expression. Highly conserved, these small RNAs appear to regulate nearly every aspect of eukaryotic biology. Perturbation of miRNA expression has been correlated ... ...

    Abstract Within the last 15 years, microRNAs (miRNAs) have emerged as powerful regulators of gene expression. Highly conserved, these small RNAs appear to regulate nearly every aspect of eukaryotic biology. Perturbation of miRNA expression has been correlated with cancer and, more recently, a variety of diseases; however, the more striking observation is that manipulation of miRNA levels can control disease phenotypes. Hence, the race to bring the first miRNA therapeutic to the market has begun. This review provides an overview of the history and mechanism of miRNAs, the ongoing efforts to develop miRNA therapies, and the nucleic acid technologies that may be key to the success of a miRNA therapeutic.
    MeSH term(s) Animals ; Gene Transfer Techniques ; Humans ; MicroRNAs/antagonists & inhibitors ; MicroRNAs/chemistry ; MicroRNAs/metabolism ; MicroRNAs/therapeutic use
    Chemical Substances MicroRNAs
    Language English
    Publishing date 2010-08
    Publishing country Netherlands
    Document type Journal Article ; Review
    ZDB-ID 1228429-4
    ISSN 1878-5875 ; 1357-2725
    ISSN (online) 1878-5875
    ISSN 1357-2725
    DOI 10.1016/j.biocel.2010.03.003
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  2. Article ; Online: Circulating microRNAs to identify human heart failure.

    Seto, Anita G / van Rooij, Eva

    European journal of heart failure

    2012  Volume 14, Issue 2, Page(s) 118–119

    MeSH term(s) Female ; Heart Failure, Systolic/genetics ; Humans ; Male ; MicroRNAs/blood
    Chemical Substances MicroRNAs
    Language English
    Publishing date 2012-02
    Publishing country England
    Document type Comment ; Editorial
    ZDB-ID 1483672-5
    ISSN 1879-0844 ; 1388-9842
    ISSN (online) 1879-0844
    ISSN 1388-9842
    DOI 10.1093/eurjhf/hfr179
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  3. Article ; Online: Cobomarsen, an Oligonucleotide Inhibitor of miR-155, Slows DLBCL Tumor Cell Growth

    Anastasiadou, Eleni / Seto, Anita G / Beatty, Xuan / Hermreck, Melanie / Gilles, Maud-Emmanuelle / Stroopinsky, Dina / Pinter-Brown, Lauren C / Pestano, Linda / Marchese, Cinzia / Avigan, David / Trivedi, Pankaj / Escolar, Diana M / Jackson, Aimee L / Slack, Frank J

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2020  Volume 27, Issue 4, Page(s) 1139–1149

    Abstract: Purpose: miRNA-155 is an oncogenic miRNA highly expressed in B-cell malignancies, particularly in the non-germinal center B-cell or activated B-cell subtype of diffuse large B-cell lymphoma (ABC-DLBCL), where it is considered a potential diagnostic and ... ...

    Abstract Purpose: miRNA-155 is an oncogenic miRNA highly expressed in B-cell malignancies, particularly in the non-germinal center B-cell or activated B-cell subtype of diffuse large B-cell lymphoma (ABC-DLBCL), where it is considered a potential diagnostic and prognostic biomarker. Thus, miR-155 inhibition represents an important therapeutic strategy for B-cell lymphomas. In this study, we tested the efficacy and pharmacodynamic activity of an oligonucleotide inhibitor of miR-155, cobomarsen, in ABC-DLBCL cell lines and in corresponding xenograft mouse models. In addition, we assessed the therapeutic efficacy and safety of cobomarsen in a patient diagnosed with aggressive ABC-DLBCL.
    Experimental design: Preclinical studies included the delivery of cobomarsen to highly miR-155-expressing ABC-DLBCL cell lines to assess any phenotypic changes, as well as intravenous injections of cobomarsen in NSG mice carrying ABC-DLBCL xenografts, to study tumor growth and pharmacodynamics of the compound over time. To begin to test its safety and therapeutic efficacy, a patient was recruited who underwent five cycles of cobomarsen treatment.
    Results: Cobomarsen decreased cell proliferation and induced apoptosis in ABC-DLBCL cell lines. Intravenous administration of cobomarsen in a xenograft NSG mouse model of ABC-DLBCL reduced tumor volume, triggered apoptosis, and derepressed direct miR-155 target genes. Finally, the compound reduced and stabilized tumor growth without any toxic effects for the patient.
    Conclusions: Our findings support the potential therapeutic application of cobomarsen in ABC-DLBCL and other types of lymphoma with elevated miR-155 expression.
    MeSH term(s) Animals ; Apoptosis/drug effects ; Apoptosis/genetics ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Proliferation/genetics ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Lymphoma, Large B-Cell, Diffuse/drug therapy ; Lymphoma, Large B-Cell, Diffuse/genetics ; Lymphoma, Large B-Cell, Diffuse/pathology ; Mice ; MicroRNAs/antagonists & inhibitors ; MicroRNAs/metabolism ; Oligonucleotides/pharmacology ; Oligonucleotides/therapeutic use ; Oligonucleotides, Antisense/pharmacology ; Oligonucleotides, Antisense/therapeutic use ; Xenograft Model Antitumor Assays
    Chemical Substances MIRN155 microRNA, human ; MicroRNAs ; Oligonucleotides ; Oligonucleotides, Antisense ; cobomarsen
    Language English
    Publishing date 2020-11-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-20-3139
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    Zs.A 4223: Show issues Location:
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  4. Article ; Online: Cobomarsen, an oligonucleotide inhibitor of miR-155, co-ordinately regulates multiple survival pathways to reduce cellular proliferation and survival in cutaneous T-cell lymphoma.

    Seto, Anita G / Beatty, Xuan / Lynch, Joshua M / Hermreck, Melanie / Tetzlaff, Michael / Duvic, Madeleine / Jackson, Aimee L

    British journal of haematology

    2018  Volume 183, Issue 3, Page(s) 428–444

    Abstract: miR-155, a microRNA associated with poor prognosis in lymphoma and leukaemia, has been implicated in the progression of mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL). In this study, we developed and tested cobomarsen ( ... ...

    Abstract miR-155, a microRNA associated with poor prognosis in lymphoma and leukaemia, has been implicated in the progression of mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL). In this study, we developed and tested cobomarsen (MRG-106), a locked nucleic acid-modified oligonucleotide inhibitor of miR-155. In MF and human lymphotropic virus type 1 (HTLV-1+) CTCL cell lines in vitro, inhibition of miR-155 with cobomarsen de-repressed direct miR-155 targets, decreased expression of multiple gene pathways associated with cell survival, reduced survival signalling, decreased cell proliferation and activated apoptosis. We identified a set of genes that are significantly regulated by cobomarsen, including direct and downstream targets of miR-155. Using clinical biopsies from MF patients, we demonstrated that expression of these pharmacodynamic biomarkers is dysregulated in MF and associated with miR-155 expression level and MF lesion severity. Further, we demonstrated that miR-155 simultaneously regulates multiple parallel survival pathways (including JAK/STAT, MAPK/ERK and PI3K/AKT) previously associated with the pathogenesis of MF, and that these survival pathways are inhibited by cobomarsen in vitro. A first-in-human phase 1 clinical trial of cobomarsen in patients with CTCL is currently underway, in which the panel of proposed biomarkers will be leveraged to assess pharmacodynamic response to cobomarsen therapy.
    MeSH term(s) Cell Line, Tumor ; Cell Survival ; Clinical Trials, Phase I as Topic ; Disease-Free Survival ; Female ; HTLV-I Infections/drug therapy ; HTLV-I Infections/metabolism ; HTLV-I Infections/mortality ; HTLV-I Infections/pathology ; Human T-lymphotropic virus 1 ; Humans ; Lymphoma, T-Cell, Cutaneous/drug therapy ; Lymphoma, T-Cell, Cutaneous/metabolism ; Lymphoma, T-Cell, Cutaneous/mortality ; Lymphoma, T-Cell, Cutaneous/pathology ; Male ; MicroRNAs/antagonists & inhibitors ; MicroRNAs/metabolism ; Oligonucleotides/pharmacology ; RNA, Neoplasm/antagonists & inhibitors ; RNA, Neoplasm/metabolism ; Survival Rate
    Chemical Substances MIRN155 microRNA, human ; MicroRNAs ; Oligonucleotides ; RNA, Neoplasm
    Language English
    Publishing date 2018-08-20
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80077-6
    ISSN 1365-2141 ; 0007-1048
    ISSN (online) 1365-2141
    ISSN 0007-1048
    DOI 10.1111/bjh.15547
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  5. Article ; Online: A MicroRNA-29 Mimic (Remlarsen) Represses Extracellular Matrix Expression and Fibroplasia in the Skin.

    Gallant-Behm, Corrie L / Piper, Joseph / Lynch, Joshua M / Seto, Anita G / Hong, Seok Jong / Mustoe, Thomas A / Maari, Catherine / Pestano, Linda A / Dalby, Christina M / Jackson, Aimee L / Rubin, Paul / Marshall, William S

    The Journal of investigative dermatology

    2018  Volume 139, Issue 5, Page(s) 1073–1081

    Abstract: MicroRNA-29 (miR-29) negatively regulates fibrosis and is downregulated in multiple fibrotic organs and tissues, including in the skin. miR-29 mimics prevent pulmonary fibrosis in mouse models but have not previously been tested in the skin. This study ... ...

    Abstract MicroRNA-29 (miR-29) negatively regulates fibrosis and is downregulated in multiple fibrotic organs and tissues, including in the skin. miR-29 mimics prevent pulmonary fibrosis in mouse models but have not previously been tested in the skin. This study aimed to identify pharmacodynamic biomarkers of miR-29 in mouse skin, to translate those biomarkers across multiple species, and to assess the pharmacodynamic activity of a miR-29b mimic (remlarsen) in a clinical trial. miR-29 biomarkers were selected based on gene function and mRNA expression using quantitative reverse transcriptase polymerase chain reaction. Those biomarkers comprised multiple collagens and other miR-29 direct and indirect targets and were conserved across species; remlarsen regulated their expression in mouse, rat, and rabbit skin wounds and in human skin fibroblasts in culture, while a miR-29 inhibitor reciprocally regulated their expression. Biomarker expression translated to clinical proof-of-mechanism; in a double-blinded, placebo-randomized, within-subject controlled clinical trial of single and multiple ascending doses of remlarsen in normal healthy volunteers, remlarsen repressed collagen expression and the development of fibroplasia in incisional skin wounds. These results suggest that remlarsen may be an effective therapeutic to prevent formation of a fibrotic scar (hypertrophic scar or keloid) or to prevent cutaneous fibrosis, such as scleroderma.
    MeSH term(s) Animals ; Biopsy, Needle ; Disease Models, Animal ; Extracellular Matrix/drug effects ; Extracellular Matrix/metabolism ; Fibrosis/genetics ; Fibrosis/pathology ; Gene Expression Regulation ; Humans ; Immunohistochemistry ; Mice ; MicroRNAs/genetics ; MicroRNAs/pharmacology ; Prospective Studies ; Skin Diseases/drug therapy ; Skin Diseases/genetics ; Skin Diseases/pathology ; Treatment Outcome
    Chemical Substances MIRN29 microRNA, mouse ; MIRN29a microRNA, human ; MicroRNAs
    Language English
    Publishing date 2018-11-22
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 80136-7
    ISSN 1523-1747 ; 0022-202X
    ISSN (online) 1523-1747
    ISSN 0022-202X
    DOI 10.1016/j.jid.2018.11.007
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  6. Article: The coming of age for Piwi proteins.

    Seto, Anita G / Kingston, Robert E / Lau, Nelson C

    Molecular cell

    2007  Volume 26, Issue 5, Page(s) 603–609

    Abstract: Piwi proteins, a subfamily of Argonaute (Ago) proteins, have recently been shown to bind endogenous small RNAs. However, differences between Ago proteins (which bind microRNAs and small interfering RNAs) and Piwi proteins and Piwi-interacting RNAs ( ... ...

    Abstract Piwi proteins, a subfamily of Argonaute (Ago) proteins, have recently been shown to bind endogenous small RNAs. However, differences between Ago proteins (which bind microRNAs and small interfering RNAs) and Piwi proteins and Piwi-interacting RNAs (piRNAs) suggest novel functions for Piwi proteins. Here, we highlight the recent progress in understanding Piwi function and the implications for germline and stem cell development.
    MeSH term(s) Animals ; Epigenesis, Genetic ; Female ; Gene Silencing ; Germ Cells/cytology ; Germ Cells/metabolism ; Humans ; Male ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Models, Biological ; Phylogeny ; Proteins/classification ; Proteins/genetics ; Proteins/metabolism ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; Stem Cells/cytology ; Stem Cells/metabolism
    Chemical Substances MicroRNAs ; Proteins ; RNA, Small Interfering
    Language English
    Publishing date 2007-06-08
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2007.05.021
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  7. Article ; Online: The Efficacy of Cardiac Anti-miR-208a Therapy Is Stress Dependent.

    Eding, Joep E C / Demkes, Charlotte J / Lynch, Joshua M / Seto, Anita G / Montgomery, Rusty L / Semus, Hillary M / Jackson, Aimee L / Isabelle, Marc / Chimenti, Stefano / van Rooij, Eva

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

    2017  Volume 25, Issue 3, Page(s) 694–704

    Abstract: MicroRNAs (miRNAs) are important regulators of biology and disease. Recent animal efficacy studies validate the therapeutic benefit of miRNA modulation and underscore the therapeutic value of miRNA-targeting oligonucleotides. However, whether disease ... ...

    Abstract MicroRNAs (miRNAs) are important regulators of biology and disease. Recent animal efficacy studies validate the therapeutic benefit of miRNA modulation and underscore the therapeutic value of miRNA-targeting oligonucleotides. However, whether disease conditions (stress) influence the pharmacological effects of an anti-miR is currently unknown. To study the effect of disease on target regulation after anti-miR treatment, we injected animals with anti-miR-208a, a synthetic oligonucleotide that inhibits the cardiomyocyte-specific miR-208a. Our data indicate that the presence of stress increases the number of regulated miR-208a targets, and that higher stress levels correlate with stronger target derepression. Additionally, the type of stress also influences which targets are regulated upon miR-208a inhibition. Studies in a large animal model indicate a similar stress-dependent anti-miR effect. Subsequent in vitro studies suggest that the influence of stress on anti-miR efficacy depends at least in part on increased cellular anti-miR uptake. These data indicate that the pharmacological effect of anti-miRs is stronger under disease conditions, and that both the type and severity of disease determine the therapeutic outcome. These facts will be important for assessing the therapeutic dose and predicting the therapeutic outcome when applying anti-miRs in a clinical setting.
    MeSH term(s) Animals ; Antagomirs/genetics ; Cells, Cultured ; Gene Expression Profiling ; Gene Expression Regulation ; Male ; MicroRNAs/genetics ; Myocytes, Cardiac/metabolism ; RNA Interference ; Rats ; Stress, Physiological/genetics ; Swine
    Chemical Substances Antagomirs ; MIRN208 microRNA, rat ; MicroRNAs
    Language English
    Publishing date 2017-03-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2010592-7
    ISSN 1525-0024 ; 1525-0016
    ISSN (online) 1525-0024
    ISSN 1525-0016
    DOI 10.1016/j.ymthe.2017.01.012
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    Zs.A 5640: Show issues Location:
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  8. Article: Development of the Preferred Components for Co-Design in Research Guideline and Checklist: Protocol for a Scoping Review and a Modified Delphi Process.

    Munce, Sarah Ep / Steele Gray, Carolyn / Pomeroy, Beverley Claire / Bayley, Mark / Kokorelias, Kristina Marie / Luong, Dorothy / Biddiss, Elaine / Cave, Trish / Bragge, Peter / Chew-Graham, Carolyn A / Colquhoun, Heather / Dadich, Ann / Dainty, Katie N / Elliott, Mark / Feng, Patrick / Goldhar, Jodeme / Hamilton, Clayon B / Harvey, Gillian / Kastner, Monika /
    Kothari, Anita / Langley, Joe / Jeffs, Lianne / Masterson, Daniel / Nelson, Michelle LA / Perrier, Laure / Riley, John / Sellen, Kate / Seto, Emily / Simpson, Robert / Staniszewska, Sophie / Srinivasan, Vasanthi / Straus, Sharon E / Tricco, Andrea C / Kuluski, Kerry

    JMIR research protocols

    2023  Volume 12, Page(s) e50463

    Abstract: Background: There is increasing evidence that co-design can lead to more engaging, acceptable, relevant, feasible, and even effective interventions. However, no guidance is provided on the specific designs and associated methods or methodologies ... ...

    Abstract Background: There is increasing evidence that co-design can lead to more engaging, acceptable, relevant, feasible, and even effective interventions. However, no guidance is provided on the specific designs and associated methods or methodologies involved in the process. We propose the development of the Preferred Components for Co-design in Research (PRECISE) guideline to enhance the consistency, transparency, and quality of reporting co-design studies used to develop complex health interventions.
    Objective: The aim is to develop the first iteration of the PRECISE guideline. The purpose of the PRECISE guideline is to improve the consistency, transparency, and quality of reporting on studies that use co-design to develop complex health interventions.
    Methods: The aim will be achieved by addressing the following objectives: to review and synthesize the literature on the models, theories, and frameworks used in the co-design of complex health interventions to identify their common elements (components, values or principles, associated methods and methodologies, and outcomes); and by using the results of the scoping review, prioritize the co-design components, values or principles, associated methods and methodologies, and outcomes to be included in the PRECISE guideline.
    Results: The project has been funded by the Canadian Institutes of Health Research.
    Conclusions: The collective results of this project will lead to a ready-to-implement PRECISE guideline that outlines a minimum set of items to include when reporting the co-design of complex health interventions. The PRECISE guideline will improve the consistency, transparency, and quality of reports of studies. Additionally, it will include guidance on how to enact or enable the values or principles of co-design for meaningful and collaborative solutions (interventions). PRECISE might also be used by peer reviewers and editors to improve the review of manuscripts involving co-design. Ultimately, the PRECISE guideline will facilitate more efficient use of new results about complex health intervention development and bring better returns on research investments.
    International registered report identifier (irrid): PRR1-10.2196/50463.
    Language English
    Publishing date 2023-10-30
    Publishing country Canada
    Document type Journal Article
    ZDB-ID 2719222-2
    ISSN 1929-0748
    ISSN 1929-0748
    DOI 10.2196/50463
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  9. Article ; Online: Plasma microRNAs serve as biomarkers of therapeutic efficacy and disease progression in hypertension-induced heart failure.

    Dickinson, Brent A / Semus, Hillary M / Montgomery, Rusty L / Stack, Christianna / Latimer, Paul A / Lewton, Steven M / Lynch, Joshua M / Hullinger, Thomas G / Seto, Anita G / van Rooij, Eva

    European journal of heart failure

    2013  Volume 15, Issue 6, Page(s) 650–659

    Abstract: Aims: Recent studies have shown that microRNAs (miRNAs), besides being potent regulators of gene expression, can additionally serve as circulating biomarkers of disease. The aim of this study is to determine if plasma miRNAs can be used as indicators of ...

    Abstract Aims: Recent studies have shown that microRNAs (miRNAs), besides being potent regulators of gene expression, can additionally serve as circulating biomarkers of disease. The aim of this study is to determine if plasma miRNAs can be used as indicators of disease progression or therapeutic efficacy in hypertension-induced heart disease.
    Methods and results: In order to define circulating miRNAs that change during hypertension-induced heart failure and that respond to therapeutic treatment, we performed miRNA arrays on plasma RNA from hypertensive rats that show signs of heart failure. Array analysis indicated that approximately one-third of the miRNAs on the array are detectable in plasma. Quantitative real-time polymerase chain reaction (PCR) analysis for a selected panel of miRNAs indicated that circulating levels of miR-16, miR-20b, miR-93, miR-106b, miR-223, and miR-423-5p were significantly increased in response to hypertension-induced heart failure, while this effect was blunted in response to treatment with antimiR-208a as well as an ACE inhibitor. Moreover, treatment with antimiR-208a resulted in a dramatic increase in one miRNA, miR-19b. A time course study indicated that several of these miRNA changes track with disease progression.
    Conclusions: Circulating levels of miRNAs are responsive to therapeutic interventions and change during the progression of hypertension-induced heart disease.
    MeSH term(s) Angiotensin-Converting Enzyme Inhibitors/therapeutic use ; Animals ; Biomarkers/blood ; Captopril/therapeutic use ; Disease Models, Animal ; Disease Progression ; Enzyme-Linked Immunosorbent Assay ; Gene Expression Profiling ; Heart Failure/chemically induced ; Heart Failure/diagnosis ; Heart Failure/drug therapy ; Hypertension/chemically induced ; Hypertension/diagnosis ; Hypertension/drug therapy ; Male ; MicroRNAs/blood ; MicroRNAs/genetics ; Natriuretic Peptide, Brain/blood ; Oligonucleotide Array Sequence Analysis ; Rats ; Rats, Inbred Dahl ; Rats, Sprague-Dawley ; Real-Time Polymerase Chain Reaction ; Sodium Chloride/toxicity ; Treatment Outcome
    Chemical Substances Angiotensin-Converting Enzyme Inhibitors ; Biomarkers ; MicroRNAs ; Natriuretic Peptide, Brain (114471-18-0) ; Sodium Chloride (451W47IQ8X) ; Captopril (9G64RSX1XD)
    Language English
    Publishing date 2013-06
    Publishing country England
    Document type Journal Article
    ZDB-ID 1483672-5
    ISSN 1879-0844 ; 1388-9842
    ISSN (online) 1879-0844
    ISSN 1388-9842
    DOI 10.1093/eurjhf/hft018
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  10. Article ; Online: MicroRNA-143 Activation Regulates Smooth Muscle and Endothelial Cell Crosstalk in Pulmonary Arterial Hypertension.

    Deng, Lin / Blanco, Francisco J / Stevens, Hannah / Lu, Ruifang / Caudrillier, Axelle / McBride, Martin / McClure, John D / Grant, Jenny / Thomas, Matthew / Frid, Maria / Stenmark, Kurt / White, Kevin / Seto, Anita G / Morrell, Nicholas W / Bradshaw, Angela C / MacLean, Margaret R / Baker, Andrew H

    Circulation research

    2015  Volume 117, Issue 10, Page(s) 870–883

    Abstract: Rationale: The pathogenesis of pulmonary arterial hypertension (PAH) remains unclear. The 4 microRNAs representing the miR-143 and miR-145 stem loops are genomically clustered.: Objective: To elucidate the transcriptional regulation of the miR-143/ ... ...

    Abstract Rationale: The pathogenesis of pulmonary arterial hypertension (PAH) remains unclear. The 4 microRNAs representing the miR-143 and miR-145 stem loops are genomically clustered.
    Objective: To elucidate the transcriptional regulation of the miR-143/145 cluster and the role of miR-143 in PAH.
    Methods and results: We identified the promoter region that regulates miR-143/145 microRNA expression in pulmonary artery smooth muscle cells (PASMCs). We mapped PAH-related signaling pathways, including estrogen receptor, liver X factor/retinoic X receptor, transforming growth factor-β (Smads), and hypoxia (hypoxia response element), that regulated levels of all pri-miR stem loop transcription and resulting microRNA expression. We observed that miR-143-3p is selectively upregulated compared with miR-143-5p during PASMC migration. Modulation of miR-143 in PASMCs significantly altered cell migration and apoptosis. In addition, we found high abundance of miR-143-3p in PASMC-derived exosomes. Using assays with pulmonary arterial endothelial cells, we demonstrated a paracrine promigratory and proangiogenic effect of miR-143-3p-enriched exosomes from PASMC. Quantitative polymerase chain reaction and in situ hybridization showed elevated expression of miR-143 in calf models of PAH and in samples from PAH patients. Moreover, in contrast to our previous findings that had not supported a therapeutic role in vivo, we now demonstrate a protective role of miR-143 in experimental pulmonary hypertension in vivo in miR-143-/- and anti-miR-143-3p-treated mice exposed to chronic hypoxia in both preventative and reversal settings.
    Conclusions: MiR-143-3p modulated both cellular and exosome-mediated responses in pulmonary vascular cells, whereas inhibition of miR-143-3p blocked experimental pulmonary hypertension. Taken together, these findings confirm an important role for the miR-143/145 cluster in PAH pathobiology.
    MeSH term(s) Animals ; Arterial Pressure ; Binding Sites ; Case-Control Studies ; Cattle ; Cell Communication ; Cell Movement ; Endothelial Cells/metabolism ; Endothelial Cells/pathology ; Exosomes/metabolism ; Female ; Gene Expression Regulation ; HeLa Cells ; Humans ; Hypertension, Pulmonary/genetics ; Hypertension, Pulmonary/metabolism ; Hypertension, Pulmonary/pathology ; Hypertension, Pulmonary/physiopathology ; Hypertension, Pulmonary/prevention & control ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Muscle, Smooth, Vascular/metabolism ; Muscle, Smooth, Vascular/pathology ; Muscle, Smooth, Vascular/physiopathology ; Myocytes, Smooth Muscle/metabolism ; Myocytes, Smooth Muscle/pathology ; Promoter Regions, Genetic ; Pulmonary Artery/metabolism ; Pulmonary Artery/pathology ; Pulmonary Artery/physiopathology ; Signal Transduction ; Time Factors ; Transcription Factors/metabolism ; Transfection ; Vascular Remodeling ; Ventricular Function, Right ; Ventricular Pressure
    Chemical Substances MIRN143 microRNA, human ; MIRN145 microRNA, human ; MIRN145a microRNA, mouse ; MicroRNAs ; MIRN143 microRNA, mouse ; Transcription Factors
    Language English
    Publishing date 2015-08-26
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80100-8
    ISSN 1524-4571 ; 0009-7330 ; 0931-6876
    ISSN (online) 1524-4571
    ISSN 0009-7330 ; 0931-6876
    DOI 10.1161/CIRCRESAHA.115.306806
    Database MEDical Literature Analysis and Retrieval System OnLINE

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