New Peptide Toxin-Derived KV1.3 Channel Inhibitor Publication in the British Journal of Pharmacology

We have a new publication in the British Journal of Pharmacology that looks at two peptide toxin-derived selective KV1.3 channel inhibitors (HsTX[R14A] and [EWSS]ShK) to determine the role in KV1.3 channels and Angiotensin II‐induced hypertension.  Access the publication at this link: https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.15407

KV1.3 Channels are Novel Determinants of Macrophage‐Dependent Endothelial Dysfunction in a Mouse Model with Angiotensin II‐Induced Hypertension

Abstract

Background and Purpose

KV1.3 channels are expressed in vascular smooth muscle cells (VSMCs), where they contribute to proliferation rather than contraction and participate in vascular remodeling. KV1.3 channels are also expressed in macrophages, where they assemble with KV1.5 channels (KV1.3/KV1.5), whose activation generates a KV current. In macrophages, the KV1.3/KV1.5 ratio is increased by classical activation (M1). Whether these channels are involved in angiotensin II (AngII)‐induced vascular remodeling, and whether they can modulate the macrophage phenotype in hypertension, remains unknown. We characterized the role of KV1.3 channels in vascular damage in hypertension.

Experimental Approach

We used AngII‐infused mice treated with two selective KV1.3 channel inhibitors (HsTX[R14A] and [EWSS]ShK). Vascular function and structure were measured using wire and pressure myography, respectively. VSMC and macrophage electrophysiology were studied using the patch‐clamp technique; gene expression was analysed using RT‐PCR.

Key Results

AngII increased KV1.3 channel expression in mice aorta and peritoneal macrophages which was abolished by HsTX[R14A] treatment. KV1.3 inhibition did not prevent hypertension, vascular remodelling, or stiffness but corrected AngII‐induced macrophage infiltration and endothelial dysfunction in the small mesenteric arteries and/or aorta, via a mechanism independent of electrophysiological changes in VSMCs. AngII modified the electrophysiological properties of peritoneal macrophages, indicating an M1‐like activated state, with enhanced expression of proinflammatory cytokines that induced endothelial dysfunction. These effects were prevented by KV1.3 blockade.

Conclusions and Implications

We unravelled a new role for KV1.3 channels in the macrophage‐dependent endothelial dysfunction induced by AngII in mice which might be due to modulation of macrophage phenotype.