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Physiol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>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<jats:sub>v<\/jats:sub>1.3 blockers inhibit the development of intimal hyperplasia, thereby preventing restenosis. This inhibition was enhanced in a mouse model of T2DM, where systemic K<jats:sub>v<\/jats:sub>1.3 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<jats:sub>v<\/jats:sub>1.3 channels, to explore their contribution to vascular disease and their potential role as targets to ameliorate T2DM vascular risk.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>Male and female BPH mice fed on high-fat diet (HFD) develop metabolic syndrome (MetS) and T2DM. mRNA levels of several K<jats:sup>+<\/jats:sup> channels (K<jats:sub>V<\/jats:sub>1.3, K<jats:sub>Ca<\/jats:sub>3.1, K<jats:sub>ir<\/jats:sub>2.1) and macrophage markers (TNF\u03b1, NOS2, CD36) were analyzed. The MMe phenotype associated with increased CD36 expression. Channel-specific fingerprinting highlights a gender-specific increase of K<jats:sub>V<\/jats:sub>1.3 mRNA fold change in LPS stimulated macrophages from HFD compared to standard diet (SD). K<jats:sub>V<\/jats:sub>1.3 functional expression was also significantly increased after LPS stimulation in female HFD macrophages compared to SD. Functional studies showed that macrophage's K<jats:sub>V<\/jats:sub>1.3 channels of BPH female mice did not contribute to phagocytosis or metabolic profile but were relevant in cell migration rate.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphys.2024.1487775","type":"journal-article","created":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T11:39:44Z","timestamp":1731497984000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["A sex-dependent role of Kv1.3 channels from macrophages in metabolic syndrome"],"prefix":"10.3389","volume":"15","author":[{"given":"Diego A.","family":"Peraza","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc\u00eda","family":"Benito-Salamanca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Moreno-Estar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esperanza","family":"Alonso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 R.","family":"L\u00f3pez-L\u00f3pez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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