SKA-31, an activator of Ca2+-activated K+ channels, improves cardiovascular function in aging.

Aging represents an independent risk factor for the development of cardiovascular disease, and is associated with complex structural and functional alterations in the vasculature, such as endothelial dysfunction. Small- and intermediate-conductance, Ca2+-activated K+ channels (KCa2.3 and KCa3.1, respectively) are prominently expressed in the vascular endothelium, and pharmacological activators of these channels induce robust vasodilation upon acute exposure in isolated arteries and intact animals. However, the effects of prolonged in vivo administration of such compounds are unknown. In our study, we hypothesized that such treatment would ameliorate aging-related cardiovascular deficits. Aged (∼18 months) male Sprague Dawley rats were treated daily with either vehicle or the KCa channel activator SKA-31 (10 mg/kg, intraperitoneal injection; n = 6/group) for 8 weeks, followed by echocardiography, arterial pressure myography, immune cell and plasma cytokine characterization, and tissue histology. Our results show that SKA-31 administration improved endothelium-dependent vasodilation, reduced agonist-induced vascular contractility, and prevented the aging-associated declines in cardiac ejection fraction, stroke volume and fractional shortening, and further improved the expression of endothelial KCa channels and associated cell signalling components to levels similar to those observed in young male rats (∼5 months at end of study). SKA-31 administration did not promote pro-inflammatory changes in either T cell populations or plasma cytokines/chemokines, and we observed no overt tissue histopathology in heart, kidney, aorta, brain, liver and spleen. SKA-31 treatment in young rats had little to no effect on vascular reactivity, select protein expression, tissue histology, plasma cytokines/chemokines or immune cell properties. Collectively, these data demonstrate that administration of the KCa channel activator SKA-31 improved aging-related cardiovascular function, without adversely affecting the immune system or promoting tissue toxicity.

Pharmacologic targeting of endothelial Ca2+-activated K+ channels: A strategy to improve cardiovascular function.

Endothelial small and intermediate-conductance, Ca2+-activated K+ channels (KCa2.3 and KCa3.1, respectively) play an important role in the regulation of vascular function and systemic blood pressure. Growing evidence indicates that they are intimately involved in agonist-evoked vasodilation of small resistance arteries throughout the circulation. Small molecule activators of KCa2.x and 3.1 channels, such as SKA-31, can acutely inhibit myogenic tone in isolated resistance arteries, induce effective vasodilation in intact vascular beds, such as the coronary circulation, and acutely decrease systemic blood pressure in vivo. The blood pressure-lowering effect of SKA-31, and early indications of improvement in endothelial dysfunction suggest that endothelial KCa channel activators could eventually be developed into a new class of endothelial targeted agents to combat hypertension or atherosclerosis. This review summarises recent insights into the activation of endothelial Ca2+ activated K+ channels in various vascular beds, and how tools, such as SKA-31, may be beneficial in disease-related conditions.

Endothelial Cell Focal Adhesion Regulates Transendothelial Migration and Subendothelial Crawling of T Cells.

Leukocytes circulating in the blood stream leave out of blood vessels and infiltrate into inflamed tissues to perform immune responses. Endothelial cells (ECs) lining interior of the post-capillary venules regulate various steps of leukocyte extravasation. In response to inflammatory signals, ECs upregulate adhesion molecules and produce/present chemokines to support firm adhesion and intraluminal crawling of leukocytes. They also remodel junctions to facilitate leukocyte transendothelial migration (TEM). While roles of apical/lateral components of EC layers in regulating leukocyte extravasation have been extensively investigated, relatively little attention has been paid to the basal part of EC layers comprising subendothelial spaces. In this study, we employed interference reflection microscopy (IRM), a microscopy technique specialized for label-free visualization of cell-substrate contact, to study detailed dynamic interactions between basal part of ECs and T cells underneath EC monolayer. For TEM, T cells on EC monolayer extended protrusions through junctions to explore subendothelial spaces, and EC focal adhesions (EC-FAs) acted as physical barrier for the protrusion. Therefore, preferential TEM occurred through junctions where near-junction focal adhesion (NJ-FA) density of ECs was low. After TEM, T cells performed subendothelial crawling (SEC) with flattened morphology and reduced migration velocity due to tight confinement. T cell SEC mostly occurred through gaps formed in between EC-FAs with minimally breaking EC-FAs. Tumor necrosis factor-α (TNF-α) treatment significantly loosened confinement in subendothelial spaces and reduced NJ-FA density of ECs, thus remodeled basal part of EC layer to facilitate leukocyte extravasation.

MgO nano-facet embedded silver-based dielectric/metal/dielectric transparent electrode.

We replace Indium Tin Oxide (ITO) with an MgO nano-facet Embedded WO(3)/Ag/WO(3)(WAW) multilayer for electrodes of high efficiency OLEDs. WAW shows higher values for transmittance (93%) and conductivity (1.3×10(5) S/cm) than those of ITO. Moreover, WAW shows higher transmittance (92.5%) than that of ITO (86.4%) in the blue region (<500 nm). However, due to the large difference in refractive indices (n) of glass (n=1.55) and WO(3) (n=1.95), the incident light has a small critical angle (52°). Thus, the generated light is confined by the glass/WAW interface, resulting in low light outcoupling efficiency (~20%). This can be enhanced by using a nano-facet structured MgO (n=1.73) layer and a ZrO(2) (n=1.84) layer as a graded index layer. Using these optimized electrodes, ITO-free, OLEDs with various emission wavelengths have been produced. The luminance of OLEDs using MgO/ZrO(2)/WAW layers is enhanced by 24% compared to that of devices with ITO.