HIV-Tat induces a decrease in I Kr and I Ks via reduction in phosphatidylinositol-(4,5)-bisphosphate availability - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Journal of Molecular and Cellular Cardiology Year : 2016

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

Kazem Zibara

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
Fichier principal
Vignette du fichier
JMCC9719R1 sumitted PDF 2.pdf (10.49 Mo) Télécharger le fichier
Origin : Files produced by the author(s)
Loading...

Dates and versions

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

Identifiers

Cite

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⟩
1692 View
985 Download

Altmetric

Share

Gmail Facebook X LinkedIn More