A sex-dependent role of Kv1.3 channels from macrophages in metabolic syndrome.

Introduction: Coronary artery disease (CAD) is the foremost single cause of mortality and disability globally. Patients with type 2 diabetes (T2DM) have a higher incidence of CAD, and poorer prognosis. The low-grade inflammation associated to T2DM contributes to increased morbidity and worst outcomes after revascularization. Inflammatory signaling in the vasculature supports endothelial dysfunction, leukocyte infiltration, and macrophage activation to a metabolic disease (MMe) specific phenotype, which could contribute to the metabolic disorders and ascular damage in T2DM. We have previously found that K_v1.3 blockers inhibit the development of intimal hyperplasia, thereby preventing restenosis. This inhibition was enhanced in a mouse model of T2DM, where systemic K_v1.3 blockers administration also improve metabolic dysfunction by acting on unidentified cellular targets other than vascular smooth muscle. Here we characterize the MMe phenotype in our T2DM model with a focus on macrophage K_v1.3 channels, to explore their contribution to vascular disease and their potential role as targets to ameliorate T2DM vascular risk. Methods and Results: Male and female BPH mice fed on high-fat diet (HFD) develop metabolic syndrome (MetS) and T2DM. mRNA levels of several K⁺ channels (K_V1.3, K_Ca3.1, K_ir2.1) and macrophage markers (TNFα, NOS2, CD36) were analyzed. The MMe phenotype associated with increased CD36 expression. Channel-specific fingerprinting highlights a gender-specific increase of K_V1.3 mRNA fold change in LPS stimulated macrophages from HFD compared to standard diet (SD). K_V1.3 functional expression was also significantly increased after LPS stimulation in female HFD macrophages compared to SD. Functional studies showed that macrophage's K_V1.3 channels of BPH female mice did not contribute to phagocytosis or metabolic profile but were relevant in cell migration rate. Conclusion: Altogether, our data suggest that by inhibiting macrophage infiltration, Kv1.3 blockers could contribute to disrupt the vicious cycle of inflammation and insulin resistance, offering a novel approach to prevent MetS, T2DM and its associated cardiovascular complications in females. [ABSTRACT FROM AUTHOR]