Background: Resolution of inflammation is orchestrated by specialized proresolving lipid mediators (SPMs), and this would be impaired in some cardiovascular diseases. Among SPMs, resolvins (Rv) have beneficial effects in cardiovascular pathologies, but little is known about their effect on cardiovascular damage in hypertension. Methods: Aorta, small mesenteric arteries, heart, and peritoneal macrophages were taken from C57BL/6J mice, infused or not with angiotensin II (AngII; 1.44 mg/kg/day, 14 days) in presence or absence of resolvin D2 (RvD2) (100 ng/mice, every second day) starting 1 day before or 7 days after AngII infusion. Results: Enzymes and receptors involved in SPMs biosynthesis and signaling were increased in aorta or heart from AngII-infused mice. We also observed a differential regulation of SPMs in heart from these mice. Preventive treatment with RvD2 partially avoided AngII-induced hypertension and protected the heart and large and small vessels against functional and structural alterations induced by AngII. RvD2 increased the availability of vasoprotective factors, modified SPMs profile, decreased cardiovascular fibrosis, and increased the infiltration of pro-resolving macrophages. When administered in hypertensive animals with established cardiovascular damage, RvD2 partially improved cardiovascular function and structure, decreased fibrosis, reduced the infiltration of neutrophils, and shifted macrophage phenotype toward a pro-resolving phenotype. Conclusions: There is a disbalance between proinflammatory and resolution mediators in hypertension. RvD2 protects cardiovascular function and structure when administered before and after the development of hypertension by modulating vascular factors, fibrosis and inflammation. Activating resolution mechanisms by treatment with RvD2 may represent a novel therapeutic strategy for the treatment of hypertensive cardiovascular disease.

Ion channels are macromolecular complexes present in the plasma membrane and intracellular organelles of cells. Dysfunction of ion channels results in a group of disorders named channelopathies, which represent an extraordinary challenge for study and treatment. In this review, we will focus on voltage-gated potassium channels (K_V), specifically on the K_V4-family. The activation of these channels generates outward currents operating at subthreshold membrane potentials as recorded from myocardial cells (I_TO, transient outward current) and from the somata of hippocampal neurons (I_SA). In the heart, K_V4 dysfunctions are related to Brugada syndrome, atrial fibrillation, hypertrophy, and heart failure. In hippocampus, K_V4.x channelopathies are linked to schizophrenia, epilepsy, and Alzheimer’s disease. K_V4.x channels need to assemble with other accessory subunits (β) to fully reproduce the I_TO and I_SA currents. β Subunits affect channel gating and/or the traffic to the plasma membrane, and their dysfunctions may influence channel pharmacology. Among K_V4 regulatory subunits, this review aims to analyze the K_V4/KChIPs interaction and the effect of small molecule KChIP ligands in the A-type currents generated by the modulation of the K_V4/KChIP channel complex. Knowledge gained from structural and functional studies using activators or inhibitors of the potassium current mediated by K_V4/KChIPs will better help understand the underlying mechanism involving K_V4-mediated-channelopathies, establishing the foundations for drug discovery, and hence their treatments.

The transient outward potassium current (I_tof) is generated by the activation of K_V4 channels assembled with KChIP2 and other accessory subunits (DPP6 and KCNE2). To test the hypothesis that these subunits modify the channel pharmacology, we analyzed the electrophysiological effects of (3-(2-(3-phenoxyphenyl)acetamido)-2-naphthoic acid) (IQM-266), a new KChIP2 ligand, on the currents generated by K_V4.3/KChIP2, K_V4.3/KChIP2/DPP6 and K_V4.3/KChIP2/KCNE2 channels. CHO cells were transiently transfected with cDNAs codifying for different proteins (K_V4.3/KChIP2, K_V4.3/KChIP2/DPP6 or K_V4.3/KChIP2/KCNE2), and the potassium currents were recorded using the whole-cell patch-clamp technique. IQM-266 decreased the maximum peak of K_V4.3/KChIP2, K_V4.3/KChIP2/DPP6 and K_V4.3/KChIP2/KCNE2 currents, slowing their time course of inactivation in a concentration-, voltage-, time- and use-dependent manner. IQM-266 produced an increase in the charge in K_V4.3/KChIP2 channels that was intensified when DPP6 was present and abolished in the presence of KCNE2. IQM-266 induced an activation unblocking effect during the application of trains of pulses to cells expressing K_V4.3/KChIP2 and K_V4.3/KChIP2/KCNE2, but not in K_V4.3/KChIP2/DPP6 channels. Overall, all these results are consistent with a preferential IQM-266 binding to an active closed state of Kv4.3/KChIP2 and Kv4.3/KChIP2/KCNE2 channels, whereas in the presence of DPP6, IQM-266 binds preferentially to an inactivated state. In conclusion, DPP6 and KCNE2 modify the pharmacological response of K_V4.3/KChIP2 channels to IQM-266.

Aim: The voltage‐gated Kv7.1 channel, in association with the regulatory subunit KCNE1, contributes to the I_Ks current in the heart. However, both proteins travel to the plasma membrane using different routes. While KCNE1 follows a classical Golgi‐mediated anterograde pathway, Kv7.1 is located in endoplasmic reticulum‐plasma membrane junctions (ER‐PMjs), where it associates with KCNE1 before being delivered to the plasma membrane.Methods: To characterize the channel routing to these spots we used a wide repertoire of methodologies, such as protein expression analysis (i.e. protein association and biotin labeling), confocal (i.e. immunocytochemistry, FRET, and FRAP), and dSTORM microscopy, transmission electron microscopy, proteomics, and electrophysiology.Results: We demonstrated that Kv7.1 targeted ER‐PMjs regardless of the origin or architecture of these structures. Kv2.1, a neuronal channel that also contributes to a cardiac action potential, and JPHs, involved in cardiac dyads, increased the number of ER‐PMjs in nonexcitable cells, driving and increasing the level of Kv7.1 at the cell surface. Both ER‐PMj inducers influenced channel function and dynamics, suggesting that different protein structures are formed. Although exhibiting no physical interaction, Kv7.1 resided in more condensed clusters (ring‐shaped) with Kv2.1 than with JPH4. Moreover, we found that VAMPs and AMIGO, which are Kv2.1 ancillary proteins also associated with Kv7.1. Specially, VAP B, showed higher interaction with the channel when ER‐PMjs were stimulated by Kv2.1.Conclusion: Our results indicated that Kv7.1 may bind to different structures of ER‐PMjs that are induced by different mechanisms. This variable architecture can differentially affect the fate of cardiac Kv7.1 channels.

K_V1.5 channel function is modified by different regulatory subunits. K_Vβ1.3 subunits assemble with K_V1.5 channels and induce a fast and incomplete inactivation. Inhibition of PKC abolishes the K_Vβ1.3-induced fast inactivation, decreases the amplitude of the current K_V1.5–K_Vβ1.3 and modifies their pharmacology likely due to changes in the traffic of K_V1.5–K_Vβ1.3 channels in a PKC-dependent manner. In order to analyze this hypothesis, HEK293 cells were transfected with K_V1.5–K_Vβ1.3 channels, and currents were recorded by whole-cell configuration of the patch-clamp technique. The presence of K_V1.5 in the membrane was analyzed by biotinylation techniques, live cell imaging and confocal microscopy approaches. PKC inhibition resulted in a decrease of 33 ± 7% of channels in the cell surface due to reduced recycling to the plasma membrane, as was confirmed by confocal microscopy. Live cell imaging indicated that PKC inhibition almost abolished the recycling of the K_V1.5–K_Vβ1.3 channels, generating an accumulation of channels into the cytoplasm. All these results suggest that the trafficking regulation of K_V1.5–K_Vβ1.3 channels is dependent on phosphorylation by PKC and, therefore, they could represent a clinically relevant issue, mainly in those diseases that exhibit modifications in PKC activity.