Uric Acid-Induced Enhancements of Kv1.5 Protein Expression and Channel Activity via the Akt-HSF1-Hsp70 Pathway in HL-1 Atrial Myocytes

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Author(s)

    • Taufiq Fikri
    • Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science
    • Tsuneto Motokazu
    • Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science
    • Shirayoshi Yasuaki
    • Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science
    • Saitoh Tatsuya
    • Division of Inflammation Biology, Institute for Enzyme Research, Tokushima University|Laboratory of Bioresponse Regulation, Graduate School of Pharmaceutical Sciences, Osaka University
    • Nakai Akira
    • Department of Biochemistry and Molecular Biology, Yamaguchi University School of Medicine
    • Yamamoto Kazuhiro
    • Division of Cardiovascular Medicine, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine
    • Hisatome Ichiro
    • Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science
    • Maharani Nani
    • Department of Pharmacology and Therapeutics, Faculty of Medicine Diponegoro University
    • Li Peili
    • Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science
    • Kurata Yasutaka
    • Department of Physiology II, Kanazawa Medical University Faculty of Medicine
    • Ikeda Nobuhito
    • Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science
    • Otani Naoyuki
    • Department of Clinical Pharmacology and Therapeutics, Oita University Faculty of Medicine
    • Miake Junichiro
    • Division of Cardiovascular Medicine, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine
    • Hasegawa Akira
    • Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science

Abstract

<p><b><i>Background: </i></b>Intracellular uric acid is known to increase the protein level and channel current of atrial Kv1.5; however, mechanisms of the uric acid-induced enhancement of Kv1.5 expression remain unclear. </p><p><b><i>Methods and Results: </i></b>The effects of uric acid on mRNA and protein levels of Kv1.5, as well as those of Akt, HSF1 and Hsp70, in HL-1 cardiomyocytes were studied by using qRT-PCR and Western blotting. The uptake of uric acid was measured using radio-labeled uric acid. The Kv1.5-mediated channel current was also measured by using patch clamp techniques. Uric acid up-taken by HL-1 cells significantly increased the level of Kv1.5 proteins in a concentration-dependent manner, with this increase abolished by an uric acid transporter inhibitor. Uric acid slowed degradation of Kv1.5 proteins without altering its mRNA level. Uric acid enhanced phosphorylation of Akt and HSF1, and thereby increased both transcription and translation of Hsp70; these effects were abolished by a PI3K inhibitor. Hsp70 knockdown abolished the uric acid-induced increases of Kv1.5 proteins and channel currents. </p><p><b><i>Conclusions: </i></b>Intracellular uric acid could stabilize Kv1.5 proteins through phosphorylation of Akt and HSF1 leading to enhanced expression of Hsp70. </p>

Journal

  • Circulation Journal

    Circulation Journal 83(4), 718-726, 2019

    The Japanese Circulation Society

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