RvD1 and LXA4 inhibitory effects on cardiac voltage-gated potassium channels

Abstract

The resolution of inflammation is modulated by specialized pro-resolving lipid mediators (SPMs), which can be modified in some cardiovascular diseases. Among these SPMs, RvD1 and LXA₄ prevent atrial fibrillation (AF) remodeling and cardiac hypertrophy, respectively in animal models. However, little is known about their electrophysiological effects on cardiac voltage-gated (VG) ion channels. We used the patch-clamp technique in heterologous systems and cardiomyocytes to assess the acute effects of RvD1, and LXA₄, on VG potassium currents. In silico simulations were used to predict the effect of current modulation on the atrial and ventricular action potentials (AP). RvD1 (5 nM) reduced I_Ks (channel K_V7.1/KCNE1) in COS-7 cells and guinea-pig cardiomyocytes by 50.3 ± 7.3 % and 29.9 ± 5.4 % at + 40 mV, respectively, without modifying its voltage dependence. RvD1 was more potent than LXA₄. In heterologous systems, RvD1 was also tested on I_Kur (channel K_V1.5), I_to (channel K_V4.3/KChIP2), I_Kr (channel K_V11.1), and I_K1 (channel K_ir2.1) with the largest inhibitory effect on I_Ks and I_Kr. In in silico simulations RvD1 prolonged repolarization significantly in both atrial and ventricular myocytes. All these results provide a comprehensive evaluation of RvD1 and LXA₄ on cardiac human potassium channels, at pathophysiologically relevant concentrations, being RvD1 more potent than LXA₄. The predicted effects on the AP suggest that, along with their antiinflammatory action, RvD1 may reverse AF-induced electrical remodeling in the atria by their modulation of K⁺ currents. The same action might instead contribute to ventricular functional remodeling; however, direct evidence for this is missing.