Altered K-Ca 3.1 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 Ca2+ -activated K+ channel (K(Ca)3.1) 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 K(Ca)3.1 and the therapeutic potential of TRAM-34, a selective inhibitor of K(Ca)3.1, in hypertrophic skin scar formation following burn injury. Cytosolic Ca2+ levels, the expression of K(Ca)3.1 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 K(Ca)3.1 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 Ca2+ than normal cells. K(Ca)3.1 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 K(Ca)3.1 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 K(Ca)3.1 is a novel mechanism underlying the cellular response to burn injury. Our results suggest that selective inhibition of K(Ca)3.1 by TRAM-34 has therapeutic potential against post-burn hypertrophic scar formation.