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    MicroRNA-mediated downregulation of K+ channels in pulmonary arterial hypertension

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    ajplung.00010.2019.pdf
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    Description:
    Final Accepted Manuscript
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    Author
    Babicheva, Aleksandra
    Ayon, Ramon J
    Zhao, Tengteng
    Ek Vitorin, Jose F
    Pohl, Nicole M
    Yamamura, Aya
    Yamamura, Hisao
    Quinton, Brooke A
    Ba, Manqing
    Wu, Linda
    Ravellette, Keeley S
    Rahimi, Shamin
    Balistrieri, Francesca
    Harrington, Angela
    Vanderpool, Rebecca R
    Thistlethwaite, Patricia A
    Makino, Ayako
    Yuan, Jason X-J
    Show allShow less
    Affiliation
    Univ Arizona, Dept Med
    Univ Arizona, Dept Physiol
    Issue Date
    2019-09-25
    Keywords
    KCNA5
    KCNMB1
    microRNA
    posttranscriptional regulation
    potassium channels
    
    Metadata
    Show full item record
    Publisher
    AMER PHYSIOLOGICAL SOC
    Citation
    Babicheva, A., Ayon, R. J., Zhao, T., Vitorin, J. F. E., Pohl, N. M., Yamamura, A., ... & Ravellette, K. S. (2019). MicroRNA-mediated downregulation of K+ channels in pulmonary arterial hypertension. American Journal of Physiology-Lung Cellular and Molecular Physiology.
    Journal
    AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
    Rights
    Copyright © 2020 the American Physiological Society.
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    Downregulated expression of K+ channels and decreased K+ currents in pulmonary artery smooth muscle cells (PASMC) have been implicated in the development of sustained pulmonary vasoconstriction and vascular remodeling in patients with idiopathic pulmonary arterial hypertension (IPAH). However, it is unclear exactly how K+ channels are downregulated in IPAH-PASMC. MicroRNAs (miRNAs) are small non-coding RNAs that are capable of posttranscriptionally regulating gene expression by binding to the 3'-untranslated regions of their targeted mRNAs. Here, we report that specific miRNAs are responsible for the decreased K+ channel expression and function in IPAH-PASMC. We identified 3 miRNAs (miR-29b, miR-138, and miR-222) that were highly expressed in IPAH-PASMC in comparison to normal PASMC (>2.5-fold difference). Selectively upregulated miRNAs are correlated with the decreased expression and attenuated activity of K+ channels. Overexpression of miR-29b, miR-138, or miR-222 in normal PASMC significantly decreased whole cell K+ currents and downregulated voltage-gated K+ channel 1.5 (KV1.5/KCNA5) in normal PASMC. Inhibition of miR-29b in IPAH-PASMC completely recovered K+ channel function and KV1.5 expression, while miR-138 and miR-222 had a partial or no effect. Luciferase assays further revealed that KV1.5 is a direct target of miR-29b. Additionally, overexpression of miR-29b in normal PASMC decreased large-conductance Ca2+-activated K+ (BKCa) channel currents and downregulated BKCa channel β1 subunit (BKCaβ1 or KCNMB1) expression, while inhibition of miR-29b in IPAH-PASMC increased BKCa channel activity and BKCaβ1 levels. These data indicate upregulated miR-29b contributes at least partially to the attenuated function and expression of KV and BKCa channels in PASMC from patients with IPAH.
    Note
    12 month embargo; published online: 25 September 2019
    ISSN
    1040-0605
    PubMed ID
    31553627
    DOI
    10.1152/ajplung.00010.2019
    Version
    Final accepted manuscript
    ae974a485f413a2113503eed53cd6c53
    10.1152/ajplung.00010.2019
    Scopus Count
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    UA Faculty Publications

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