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HIV Tat protein inhibits hERG K+ channels: A potential mechanism of HIV infection induced LQTs

  • Author Footnotes
    1 Authors contributed equally to this work.
    Yun-Long Bai
    Footnotes
    1 Authors contributed equally to this work.
    Affiliations
    Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin 150086, PR China
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  • Author Footnotes
    1 Authors contributed equally to this work.
    Hui-Bin Liu
    Footnotes
    1 Authors contributed equally to this work.
    Affiliations
    Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin 150086, PR China
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  • Bo Sun
    Affiliations
    Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin 150086, PR China
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  • Ying Zhang
    Affiliations
    Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin 150086, PR China
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  • Qi Li
    Affiliations
    Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin 150086, PR China
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  • Chao-Wei Hu
    Affiliations
    Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin 150086, PR China
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  • Jiu-Xin Zhu
    Affiliations
    Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin 150086, PR China
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  • Dong-Mei Gong
    Affiliations
    Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin 150086, PR China
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  • Xue Teng
    Affiliations
    Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin 150086, PR China
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  • Qin Zhang
    Affiliations
    Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin 150086, PR China
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  • Bao-Feng Yang
    Affiliations
    Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin 150086, PR China
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  • De-Li Dong
    Correspondence
    Corresponding author at: Department of Pharmacology, Harbin Medical University, Baojian Road 157, Harbin 150086, Heilongjiang Province, PR China. Tel.: +86 451 86671354; fax: +86 451 86667511.
    Affiliations
    Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin 150086, PR China
    Search for articles by this author
  • Author Footnotes
    1 Authors contributed equally to this work.

      Abstract

      HIV-infected patients have a high prevalence of long QT syndrome (LQTs). hERG K+ channel encoded by human ether-a-go-go related gene contributes to IKr K+ currents responsible for the repolarization of cardiomyocytes. Inhibition of hERG K+ channels leads to LQTs. HIV Tat protein, the virus transactivator protein, plays a pivotal role in AIDS. The aim of the present study is to examine the effects of HIV Tat protein on hERG K+ channels stably expressed in HEK293 cells. The hERG K+ currents were recorded by whole-cell patch-clamp technique and the hERG channel expression was measured by real-time PCR and Western blot techniques. HIV Tat protein at 200 ng/ml concentration showed no acute effect on hERG currents, but HIV Tat protein (200 ng/ml) incubation for 24 h significantly inhibited hERG currents. In HIV Tat incubated cells, the inactivation and the recovery time from inactivation of hERG channels were significantly changed. HIV Tat protein incubation (200 ng/ml) for 24 h had no effect on the hERG mRNA expression, but dose-dependently inhibited hERG protein expression. The MTT assay showed that HIV Tat protein at 50 ng/ml and 200 ng/ml had no effect on the cell viability. HIV Tat protein increased reactive oxygen species (ROS) generation and the inhibition of hERG channel protein expression by HIV Tat protein was prevented by antioxidant tempol. HIV Tat protein in vivo treatment reduced IKr currents and prolonged action potential duration of guinea pig cardiomyocytes. We conclude that HIV Tat protein inhibits hERG K+ currents through the inhibition of hERG protein expression, which might be the potential mechanism of HIV infection induced LQTs.

      Highlights

      • HIV Tat inhibits hERG currents after 24hrs incubation.
      • HIV Tat dose-dependently inhibits hERG protein expression.
      • HIV Tat inhibits hERG protein expression through increasing ROS generation.
      • HIV Tat reduces IKr currents and prolongs APD of guinea pig cardiomyocytes.
      • Inhibition of hERG K+ channels by HIV Tat is a potential mechanism of HIV infection induced LQTs.

      Keywords

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