Kv1.3 blocker PAP-1 alleviates psoriasis-like dermatitis in rats via dual anti-inflammatory and anti-angiogenic mechanisms

Psoriasis is a chronic inflammatory skin disorder characterized by epidermal hyperplasia, immune cell infiltration, and pathological angiogenesis. Current therapies often have safety concerns or limited long-term efficacy. The voltage-gated potassium channel Kv1.3 is upregulated in effector memory T cells and implicated in several autoimmune diseases, making its selective blockade an attractive therapeutic strategy. While PAP-1, a selective Kv1.3 channel blocker, shows therapeutic potential, its precise mechanisms in psoriasis-like conditions have been incompletely understood, particularly regarding its impact on angiogenesis.

Researchers investigated the effects of PAP-1 in a psoriasis-like dermatitis model induced by imiquimod (IMQ) in male rats. PAP-1 was administered both preventively and therapeutically. Key endpoints included assessment of skin lesion severity and splenomegaly. They performed RNA sequencing to identify gene expression changes, measured pro-inflammatory cytokines and vascular markers, and conducted HUVEC (human umbilical vein endothelial cell) assays to evaluate proliferation, migration, invasion, and tube formation induced by VEGF-A. Mechanistic studies included assessing Kv1.3 currents and expression, complemented by Cryo-EM structural analysis.

PAP-1 markedly attenuated imiquimod (IMQ)-induced psoriasis-like skin lesions and reduced splenomegaly in male rats, demonstrating both preventive and therapeutic efficacy. RNA sequencing revealed that PAP-1 downregulated genes associated with inflammation and angiogenesis, accompanied by decreased levels of pro-inflammatory cytokines and vascular markers in the treated skin. PAP-1 also inhibited VEGF-A-induced HUVEC proliferation, migration, invasion, and tube formation, directly impacting angiogenesis. Mechanistically, PAP-1 not only blocked Kv1.3 currents, but also suppressed Kv1.3 expression in the skin of IMQ-induced psoriasis-like male rats and VEGF-A-induced HUVECs.