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MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension

Alexander M K Rothman, Nadine D Arnold, Josephine A Pickworth

    The Journal of Clinical Investigation
    |May 24, 2016
    PubMed

    Insights

    Reduced miR-140-5p levels promote pulmonary arterial hypertension (PAH) by increasing SMURF1, a regulator of BMP signaling. Restoring miR-140-5p or inhibiting SMURF1 offers potential PAH therapies.

    Area of Science:

    • Cardiovascular Biology
    • Molecular Medicine
    • Cellular Signaling

    Background:

    • Bone morphogenetic protein (BMP) signaling loss drives pulmonary arterial hypertension (PAH) via endothelial dysfunction and smooth muscle cell proliferation.
    • MicroRNAs (miRs) regulate cellular functions, but their expression is altered in disease states like PAH.

    Purpose of the Study:

    • Investigate the role of miR-140-5p in pulmonary arterial hypertension (PAH).
    • Identify miR-140-5p targets and their involvement in BMP signaling pathways relevant to PAH pathogenesis.

    Main Methods:

    • Analysis of miR-140-5p levels in treatment-naive PAH patients and experimental models.
    • In vitro studies on pulmonary arterial smooth muscle cell (PASMC) proliferation and migration.
    • In vivo studies using nebulized miR-140-5p mimics in rat PAH models.
    • Network and pathway analysis to identify miR-140-5p targets, including SMURF1.
    • Evaluation of SMURF1 expression in human PAH tissues and its effect on BMP signaling.
    • Genetic manipulation (Smurf1 deletion) in mouse models of PAH.

    Main Results:

    • miR-140-5p levels were reduced in PAH patients and models.
    • Inhibition of miR-140-5p increased PASMC proliferation and migration.
    • Nebulized miR-140-5p mimic therapy prevented and attenuated PAH in rats.
    • SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1) was identified as a key target of miR-140-5p and a regulator of BMP signaling.
    • SMURF1 levels were elevated in human PAH tissues.
    • miR-140-5p mimic or SMURF1 knockdown modulated BMP signaling in PASMCs.
    • Smurf1 deletion protected mice against PAH development.

    Conclusions:

    • miR-140-5p is downregulated in PAH and its restoration has therapeutic potential.
    • SMURF1 is a critical mediator of PAH pathogenesis by regulating BMP signaling.
    • Both miR-140-5p and SMURF1 represent promising therapeutic targets for pulmonary arterial hypertension.

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