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lüll Endoplasmic reticulum Ca2+ depletion induces endothelial cell apoptosis independently of caspase-12 Nakano T; Watanabe H; Ozeki M; Asai M; Katoh H; Satoh H; Hayashi HCardiovasc Res 2006[Mar]; 69 (4): 908-15OBJECTIVE: Apoptosis of endothelial cells is considered an initial step in the development of atherosclerosis. Recent studies have indicated that depletion of the endoplasmic reticulum (ER) Ca(2+) content plays an important role in apoptosis. Caspase-12 is a key signal in ER stress-induced apoptosis. However, it is not known whether the depletion of ER Ca(2+) is linked to caspase-12 signalling in endothelial cells. Here we have investigated the interaction of Ca(2+) signalling and caspase-12 cleavage in apoptosis of endothelial cells. METHODS: Cytosolic Ca(2+) concentration ([Ca(2+)](i)) of primary porcine aortic endothelial cells was measured using fura-2/AM. Apoptosis was assessed by DNA fragmentation, and cleavage of caspase-12 using Western blotting techniques. RESULTS: Thapsigargin (5 microM), an inhibitor of the ER Ca(2+)-ATPase, depleted ER Ca (2+) content, increased [Ca(2+)](i), cleaved caspase-12, and induced apoptosis. Bradykinin (10 nM) also increased [Ca(2+)](i) but did not cleave caspase-12 or induce apoptosis. However, when intracellular Ca(2+) was chelated with BAPTA/AM (100 microM), bradykinin caused ER Ca(2+) depletion and apoptosis without accompanying caspase-12 cleavage. A non-selective caspase inhibitor, z-VAD.fmk (100 microM), inhibited apoptosis and cleavage of caspase-12 stimulated by thapsigargin, while a calpain inhibitor, MDL 28170 (120 microM), inhibited caspase-12 cleavage but not apoptosis. CONCLUSIONS: Thus, increases in intracellular Ca(2+) concentration are not sufficient for the induction of apoptosis in endothelial cells, and ER Ca(2+) depletion appears to induce apoptosis independently of caspase-12.|Amino Acid Chloromethyl Ketones/pharmacology[MESH]|Animals[MESH]|Aorta[MESH]|Apoptosis[MESH]|Blotting, Western/methods[MESH]|Bradykinin/pharmacology[MESH]|Calcium-Transporting ATPases/antagonists & inhibitors[MESH]|Calcium/*metabolism[MESH]|Calpain/antagonists & inhibitors[MESH]|Caspase 12[MESH]|Caspase Inhibitors[MESH]|Caspases/*metabolism[MESH]|Cells, Cultured[MESH]|Chelating Agents/pharmacology[MESH]|Cytosol/metabolism[MESH]|DNA Fragmentation[MESH]|Dipeptides/pharmacology[MESH]|Egtazic Acid/analogs & derivatives/pharmacology[MESH]|Endoplasmic Reticulum/*metabolism[MESH]|Endothelial Cells/*metabolism/*pathology[MESH]|Endothelium, Vascular/metabolism[MESH]|Enzyme Inhibitors/pharmacology[MESH]|Signal Transduction/*physiology[MESH]|Swine[MESH]|Thapsigargin/pharmacology[MESH] |