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

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 LXA 4 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 LXA 4 , 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 V 7.1/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 LXA 4 . In heterologous systems, RvD1 was also tested on I Kur (channel K V 1.5), I to (channel K V 4.3/KChIP2), I Kr (channel K V 11.1), and I K1 (channel K ir 2.1) 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 LXA 4 on cardiac human potassium channels, at pathophysiologically relevant concentrations, being RvD1 more potent than LXA 4 . 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. • The resolution of inflammation is modulated by specialized pro-resolving lipid mediators (SPMs), which can be modified in some cardiovascular diseases. Moreover, RvD1 prevented atrial fibrillation (AF) and countered atrial pro-arrhythmic remodeling in animal experimental models. • Polyunsaturated fatty acids (PUFAs) (pro-resolving lipid mediators, the SPMs precursors) directly modulate voltage-gated ion channels, to the extent that they have been proposed as potential anti-arrhythmic drugs. Consequently, the regulation of ion channels produced by SPMs reported here, thus far poorly investigated, might be relevant to cardiac electrophysiology. • Resolvin D1 (RvD1) inhibits a wide array of K + currents relevant to myocardial repolarization. These findings are pathophysiologically relevant to conditions involving inflammatory and/or procoagulative states, the prerequisite for endogenous SPMs synthesis.