K_V1.3 channels are novel determinants of macrophage‐dependent endothelial dysfunction in angiotensin II‐induced hypertension in mice

Abstract

Background and Purpose: K V 1.3 channels are expressed in vascular smooth muscle cells (VSMCs), where they contribute to proliferation rather than contraction and participate in vascular remodelling. K V 1.3 channels are also expressed in macrophages, where they assemble with K V 1.5 channels (K V 1.3/K V 1.5), whose activation generates a K V current. In macrophages, the K V 1.3/K V 1.5 ratio is increased by classical activation (M1). Whether these channels are involved in angiotensin II (AngII)-induced vascular remodelling, and whether they can modulate the macrophage phenotype in hypertension, remains unknown. We characterized the role of K V 1.3 channels in vascular damage in hypertension. Experimental Approach: We used AngII-infused mice treated with two selective K V 1.3 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 K V 1.3 channel expression in mice aorta and peritoneal macrophages which was abolished by HsTX[R14A] treatment. K V 1.3 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 K V 1.3 blockade.

Resolvin D2 Attenuates Cardiovascular Damage in Angiotensin II-Induced Hypertension

“…We then used peritoneal macrophages as a model to assess changes in proinflammatory profile with potential impact in vascular function. 30 Peritoneal macrophages from AngII-infused mice exhibited altered electrophysiological properties (ie, augmented K V currents, greater use-dependent decay and an increase in the degree of inactivation together with a faster time constant of inactivation; Figure 4C and 4D; Figure S6), as previously reported for classical activated or (M1) macrophages. 31 AngII also increased the expression of Kcna3 and proinflammatory mediators such as Il1β , Il6 , and Cox2 (Figure 4E) and reduced the expression of the antioxidant enzyme, hemooxygenase 1 ( Hmox-1 ).…”

“…31,47 We have recently described that AngII increases the expression of Kcna3 gene in mice aortic perivascular adipose tissue and peritoneal macrophages where it also upregulates Kv current and M1-like cytokines participating in endothelial dysfunction. 30 Here, we found that both preventive and therapeutic treatment with RvD2 clearly restored electrophysiological properties and decreased the expression of Kcna3 and several M1 cytokines while upregulating M2 markers in peritoneal macrophages, demonstrating widespread effects of RvD2. In agreement, RvD2 addition to activated peritoneal macrophages reduced IL-1β secretion, 48 and human macrophages incubated with RvD2 displayed augmented Cd163 expression.…”

Graphene Particles Interfere with Pro‐Inflammatory Polarization of Human Macrophages: Functional and Electrophysiological Evidence

“…Previous studies have shown a close interplay between K + ‐channels and hMF polarization, with specific stoichiometries of the subunits and the resulting currents and membrane potentials. [ 47,48,63–66 ] In fact, K + ‐channels are the most complex class of voltage‐gated ion channels from both a functional and a structural standpoint. KCNA3 encodes the voltage‐gated Kv1.3 channel.…”

Interferon-stimulated gene 15, a common link of vascular damage in hypertension, obesity and aortic aneurysms

“…Además, estos monocitos/macrófagos tienen un papel causal en el desarrollo del remodelado vascular y la disfunción endotelial, puesto que diferentes tipos de ratones deficientes en macrófagos (98,(198)(199)(200) están protegidos frente al desarrollo del remodelado vascular, la disfunción endotelial y la hipertensión. Además, recientemente hemos publicado que los medios condicionados de macrófagos de ratones infundidos con Ang II inducen la disfunción endotelial a través de la liberación de IL-1b y prostaglandinas derivadas de la COX-2 (201). Los macrófagos tipo M2 también se encontraron dentro de la pared vascular después de la infusión de Ang II (202) y parecen promover la rigidez vascular y el remodelado de la MEC, incluyendo la deposición de colágeno, la fibrosis adventicial y la pérdida de elastina (202), confirmando que los macrófagos tipo M1 o M2 tienen un papel en la disfunción vascular en la hipertensión.…”