Article Dans Une Revue Journal of Molecular and Cellular Cardiology Année : 2016

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

Résumé

Patients with HIV present with a higher prevalence of QT prolongation, of which molecularbases are still not clear. Among HIV proteins, Tat serves as a transactivator that stimulatesviral genes expression and is required for efficient HIV replication. Tat is actively secretedinto the blood by infected T-cells and affects organs such as the heart. Tat has been shown toalter cardiac repolarization in animal models but how this is mediated and whether this is alsothe case in human cells is unknown. In the present study, we show that Tat transfection inheterologous expression systems led to a decrease in hERG (underlying cardiac IKr) andhuman KCNE1-KCNQ1 (underlying cardiac IKs) currents and to an acceleration of theirdeactivation. This is consistent with a decrease in available phosphatidylinositol-(4,5)-bisphosphate (PIP2). A mutant Tat, unable to bind PIP2, did not reproduce the observedeffects. 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 pluripotentstem cells-derived cardiomyocytes with Wild-type Tat reduced IKr and accelerated itsdeactivation. 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 wereexacerbated at a low pacing cycle length. Altogether, these data obtained on human K+channels both in heterologous expression systems and in human cardiomyocytes stronglysuggest that Tat sequesters PIP2, leading to a reduction of IKr and IKs, and provide a molecularmechanism for QT prolongation in HIV-infected patients.Key

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inserm-01360585 , version 1 (06-09-2016)

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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, 2016, [Epub ahead of print]. ⟨10.1016/j.yjmcc.2016.08.022⟩. ⟨inserm-01360585⟩
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