Direct protective effects of poly-unsaturated fatty acids, DHA and EPA, against activation of cardiac late sodium current

Abstract

Polyunsaturated fatty acids (PUFAs) such as docosahexaenoic and eicosapentaenoic acids (DHA, EPA) exert ischemic anti-arrhythmic effects. However, their mechanism of action remains unknown. The present study was designed to investigate their potential effect on the regulation of the late sodium current as the basis for their ischemic anti-arrhythmic activity. Human isoforms of wild-type SCN5A and DeltaKPQ-mutated cardiac sodium channels were stably transfected in HEK 293 cells and, the resulting currents were recorded using the patch clamp technique in whole cell configuration. In addition to their effect to inhibit peak I(Na), acute application of DHA and EPA blocked veratridine-induced late sodium current (late I(Na-Verat)) in a concentration--dependent manner with IC(50) values of 2.1 +/- 0.5 microM and 5.2 +/- 0.8 microM,for DHA and EPA, respectively. Channels availability was reduced, resulting in a significant leftward shift of the steadystate inactivation curve by -10.0 +/- 2.1 mV and -8.5 +/- 0.2 mV for DHA and EPA, respectively. Similar inhibitory effects of DHA and EPA were also observed on late I(Na-KPQ). In addition to their role as blocking agents of peak I(Na), DHA and EPA reduced human late I(Na). These results could explain the antiarrhythmic properties of DHA and EPA during ischemia or following ischemia-reperfusion.

Suppression of PPARβ, and DHA treatment, inhibit NaV1.5 and NHE-1 pro-invasive activities

“…Our results are in apparent contradiction with the studies which showed an acute effect of DHA or EPA on Na V 1.5 currents in HEK293 cells overexpressing the adult splice variant of SCN5A [33,44] and which suggested a direct interaction of n-3 PUFAs with a single amino acid residue N406 located in the segment 6 of domain I (DIS6) of the protein [43]. However, in those studies, currents were analyzed from adult splice variants of the SCN5A gene.…”

“…Other forms of DHA (ethyl ester and sodium salt) and higher concentrations of all three forms up to 30 μM were also tested but had no further effects (data not shown). These results obtained in cancer cells endogenously expressing nNa V 1.5 differ from currents recorded from aNaV1.5 channels overexpressed in HEK293 [33,44].…”

“…DHA reduced nNa V 1.5 current and nNa V 1.5-dependent cell invasiveness DHA inhibits nNa V 1.5 expression and breast cancer cell migration [24] as well as Na V 1.5 sodium currents from aNa V 1.5 channels overexpressed in HEK293 [33,44]. However, the potential effects of DHA on nNa V 1.5 current in breast cancer cell and nNa V 1.5-dependent cell invasiveness have not been reported so far.…”

“…Firstly, in HEK293 cells stably transfected with human adult SCN5A splice variant (aNa V 1.5), both Na V 1.5-related peak currents and veratridine-induced late currents are reduced by DHA or EPA in acute treatments, but not by monounsaturated fatty acid oleic acid (OA, 18:1n-9) or the saturated fatty acids stearic acid and palmitic acid [33,44]. Secondly, SCN5A is abnormally highly expressed as a neonatal splice variant nNa V 1.5 [18] in breast cancer tissues and in highly invasive MDA-MB-231 breast cancer cells, and it is associated with the development of metastases [9,18,46].…”

An Emerging Antiarrhythmic Target: Late Sodium Current

“…INa,L is modulated by wide variety of metabolites and second messengers. Poly-unsaturated fatty acids, like docosahexaenoic and eicosapentaenoic acids (DHA, EPA) were shown to substantially reduce both transient and late phase of INa [192]. The reduction develops from hyperpolarizing shift in SSI and activation curve decreasing the window current.…”