Altered K3.1 expression following burn injury and the therapeutic potential of TRAM-34 in post-burn hypertrophic scar formation.

Hypertrophic scars are the most common post-burn complications characterized by fibroblast proliferation and excessive extracellular matrix deposition. The intermediate-conductance Ca-activated K channel (K3.1) mediates fibroblast activation, resulting in several fibrotic diseases; however, this channel's role in the formation of post-burn hypertrophic skin scars remains unknown. Herein, we investigated the role of K3.1 and the therapeutic potential of TRAM-34, a selective inhibitor of K3.1, in hypertrophic skin scar formation following burn injury. Cytosolic Ca levels, the expression of K3.1 and hypertrophic markers, and the proliferation of skin fibroblasts obtained directly from patients with third-degree burns who consequently developed post-burn hypertrophic scars were assessed. The anti-fibrotic effect of K3.1 inhibition by TRAM-34 was evaluated in vitro (fibroblasts) and in vivo (mouse burn models). Fibroblasts from burn wounds exhibited remarkably higher levels of cytosolic Ca than normal cells. K3.1 expression was markedly higher in the membrane fraction but lower in the cytosolic fraction of burn wound fibroblasts than in normal cells. Selective inhibition of K3.1 by TRAM-34 markedly reduced not only the proliferation of burn wound fibroblasts but also the expression of hypertrophic markers in these cells. Anti-scarring molecular, histological, and visual effects of TRAM-34 were confirmed in murine burn models. Altered subcellular expression of K3.1 is a novel mechanism underlying the cellular response to burn injury. Our results suggest that selective inhibition of K3.1 by TRAM-34 has therapeutic potential against post-burn hypertrophic scar formation.