Effects of Allicin on Late Sodium Current Caused by ΔKPQ-SCN5A Mutation in HEK293 Cells

Abstract

AimThe aim was to study the effect of Allitridum (Allicin) on the heterologous expression of the late sodium current on the ΔKPQ-SCN5A mutations in HEK293 cells, with a view to screening new drugs for the treatment of long QT syndrome type 3 (LQT3).Methods and ResultsThe ΔKPQ-SCN5A plasmid was transiently transferred into HEK293 cells by liposome technology and administered by extracellular perfusion, and the sodium current was recorded by whole-cell patch-clamp technology. Application of Allicin 30 μM reduced the late sodium current (INa,L) of the Nav1.5 channel current encoded by ΔKPQ-SCN5A from 1.92 ± 0.12 to 0.65 ± 0.03 pA/pF (P < 0.01, n = 15), which resulted in the decrease of INa,L/INa,P (from 0.94% ± 0.04% to 0.32% ± 0.02%). Furthermore, treatment with Allicin could move the steady-state inactivation of the channel to a more negative direction, resulting in an increase in channel inactivation at the same voltage, which reduced the increase in the window current and further increased the inactivation of the channel intermediate state. However, it had no effect on channel steady-state activation (SSA), inactivation mechanics, and recovery dynamics after inactivation. What’s more, the Nav1.5 channel protein levels of membrane in the ΔKPQ-SCN5A mutation were enhanced from 0.49% ± 0.04% to 0.76% ± 0.02% with the effect of 30 mM Allicin, close to 0.89% ± 0.02% of the WT.ConclusionAllicin reduced the late sodium current of ΔKPQ-SCN5A, whose mechanism may be related to the increase of channel steady-state inactivation (SSI) and intermediate-state inactivation (ISI) by the drug, thus reducing the window current.

Therapeutic potentials of allicin in cardiovascular disease: advances and future directions

“…Han et al [ 75 ] indicated that allicin inhibited Cav1.2 channels by reducing the expression of channel proteins, providing a partial explanation for its inhibitory potential. Allicin also effectively inactivated the ΔKPQ-SCN5A mutant channel in congenital long QT syndrome type 3 (LQT3), thereby reducing the late sodium current of the ΔKPQ-SCN5A mutation [ 76 ]. Moreover, allicin decreased the ratio of late sodium current to peak current (INa,L/INa,P) by promoting Nav1.5 distribution on the cell membrane, resulting in therapeutic effects on LQT3.…”

Cellular Mechanisms Underlying the Cardioprotective Role of Allicin on Cardiovascular Diseases

“…The congenital long QT syndrome type 3 (LQT3) a hereditary arrhythmia is associated with mutations in the Nav1.5 channels, such as ∆KPQ. In cell culture, allicin reduced the late Na+ current (I Na,L ) of the cardiac Na+ channel ∆KPQ-SCN5A, related to the dynamics of channel steady-state inactivation (SSI) and intermediate-state inactivation (ISI) by the drug, thus reducing the window current, which suggests that allicin may be useful in LQT3 therapy [ 106 ].…”