Abstract：
Macrophages in atherosclerotic lesions accumulate large amounts of unesterified cholesterol. Excess cholesterol load leads to cell death of macrophages, which is associated with the progression of atherosclerotic lesions. Calcium depletion in the endoplasmic reticulum (ER) and subsequent pro-apoptotic aberrant calcium signaling are key events in cholesterol-induced macrophage death. Although these concepts imply cytoplasmic calcium events in cholesterol-loaded macrophages, the mechanisms linking cholesterol accumulation to cytoplasmic calcium response have been poorly investigated. Based on our previous finding that extracellularly applied cholesterol evoked robust calcium oscillations in astrocytes, a type of glial cells in the brain, we hypothesized that cholesterol accumulation in macrophages triggers cytoplasmic calcium elevation. Here, we showed that cholesterol application induces calcium transients in THP-1-derived and peritoneal macrophages. Inhibition of inositol 1,4,5-trisphosphate receptors (IP3Rs) and l-type calcium channels (LTCCs) prevented cholesterol-induced calcium transients and ameliorated cholesterol-induced macrophage death. These results suggest that cholesterol-induced calcium transients through IP3Rs and LTCCs are crucial mechanisms underlying cholesterol-induced cell death of macrophages.
摘要：
动脉粥样硬化病变中的巨噬细胞积累了大量未酯化的胆固醇。过量的胆固醇负荷导致巨噬细胞的细胞死亡，这与动脉粥样硬化病变的进展有关。内质网（ER）中的钙消耗和随后的促凋亡异常钙信号传导是胆固醇诱导的巨噬细胞死亡的关键事件。尽管这些概念暗示了胆固醇负载巨噬细胞中的细胞质钙事件，关于胆固醇积累与细胞质钙反应的相关机制研究甚少。根据我们先前的发现，细胞外应用的胆固醇会引起星形胶质细胞中强烈的钙振荡，大脑中的一种神经胶质细胞，我们假设巨噬细胞中的胆固醇积累会引发细胞质钙升高.这里,我们发现应用胆固醇诱导THP-1来源和腹膜巨噬细胞的钙瞬变。抑制肌醇1,4,5-三磷酸受体（IP3R）和1型钙通道（LTCC）可预防胆固醇诱导的钙瞬变并改善胆固醇诱导的巨噬细胞死亡。这些结果表明，胆固醇通过IP3R和LTCC诱导的钙瞬变是胆固醇诱导的巨噬细胞死亡的关键机制。
