Low calcium exacerbates endothelial cell injury by histones

Histones from dying cells promote endotheliopathy in critical illness, but mechanisms remain unclear. The role of transfusion-induced hypocalcemia is unexplored. We hypothesized that histones bind endothelial membranes via electrostatic interactions and that low Ca2+ increases toxicity by enhancing binding. Using video microscopy and flow cytometry, we assessed histone toxicity in cultured endothelial cells and blood vessels. Histones triggered rapid membrane changes and dye uptake within 40 minutes. Surprisingly, removing Ca2+ prevented Ca2+ overload but worsened membrane deformation. Elevated Ca2+ blocked histone-phospholipid interactions and damage. Low Ca2+ enhances histone binding, increasing endothelial toxicity, highlighting the need to correct hypocalcemia during resuscitation.