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HIV-Tat induces a decrease in I Kr and I Ks via reduction in phosphatidylinositol-(4,5)-bisphosphate availability

Abstract : Patients with HIV present with a higher prevalence of QT prolongation, of which molecular bases are still not clear. Among HIV proteins, Tat serves as a transactivator that stimulates viral genes expression and is required for efficient HIV replication. Tat is actively secreted into the blood by infected T-cells and affects organs such as the heart. Tat has been shown to alter cardiac repolarization in animal models but how this is mediated and whether this is also the case in human cells is unknown. In the present study, we show that Tat transfection in heterologous expression systems led to a decrease in hERG (underlying cardiac IKr) and human KCNE1-KCNQ1 (underlying cardiac IKs) currents and to an acceleration of their deactivation. This is consistent with a decrease in available phosphatidylinositol-(4,5)- bisphosphate (PIP2). A mutant Tat, unable to bind PIP2, did not reproduce the observed effects. In addition, WT-Tat had no effect on a mutant KCNQ1 which is PIP2-insensitive, further confirming the hypothesis. Twenty four-hour incubation of human induced pluripotent stem cells-derived cardiomyocytes with Wild-type Tat reduced IKr and accelerated its deactivation. Concordantly, this Tat incubation led to a prolongation of the action potential (AP) duration. Events of AP alternans were also recorded in the presence of Tat, and were exacerbated at a low pacing cycle length. Altogether, these data obtained on human K+ channels both in heterologous expression systems and in human cardiomyocytes strongly suggest that Tat sequesters PIP2, leading to a reduction of IKr and IKs, and provide a molecular mechanism for QT prolongation in HIV-infected patients. Key
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Submitted on : Tuesday, September 6, 2016 - 10:33:54 AM
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Zeineb Es-Salah-Lamoureux, Mariam Jouni, Nadjet Belbachir, Zeina Reda, Al Sayed, et al.. HIV-Tat induces a decrease in I Kr and I Ks via reduction in phosphatidylinositol-(4,5)-bisphosphate availability. Journal of Molecular and Cellular Cardiology, Elsevier, 2016, [Epub ahead of print]. ⟨10.1016/j.yjmcc.2016.08.022⟩. ⟨inserm-01360585⟩



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