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Cardiovascular Research 2006 69(4):908-915; doi:10.1016/j.cardiores.2005.11.023
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Copyright © 2005, European Society of Cardiology

Endoplasmic reticulum Ca2+ depletion induces endothelial cell apoptosis independently of caspase-12

Tomoyasu Nakanoa, Hiroshi Watanabeb,*, Mariko Ozekia, Masayoshi Asaia, Hideki Katoha, Hiroshi Satoha and Hideharu Hayashia

aDepartment of Internal Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
bDepartment of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine. 1-20-1 Handayama, Hamamatsu, 431-3192, Japan

* Corresponding author. Tel.: +81 53 435 2267; fax: +81 53 434 2910. Email address: hwat{at}hama-med.ac.jp

Objective: 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) Ca2+ 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 Ca2+ is linked to caspase-12 signalling in endothelial cells. Here we have investigated the interaction of Ca2+ signalling and caspase-12 cleavage in apoptosis of endothelial cells.

Methods: Cytosolic Ca2+ concentration ([Ca2+]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 µM), an inhibitor of the ER Ca2+-ATPase, depleted ER Ca 2+ content, increased [Ca2+]i, cleaved caspase-12, and induced apoptosis. Bradykinin (10 nM) also increased [Ca2+]i but did not cleave caspase-12 or induce apoptosis. However, when intracellular Ca2+ was chelated with BAPTA/AM (100 µM), bradykinin caused ER Ca2+ depletion and apoptosis without accompanying caspase-12 cleavage. A non-selective caspase inhibitor, z-VAD.fmk (100 µM), inhibited apoptosis and cleavage of caspase-12 stimulated by thapsigargin, while a calpain inhibitor, MDL 28170 (120 µM), inhibited caspase-12 cleavage but not apoptosis.

Conclusions: Thus, increases in intracellular Ca2+ concentration are not sufficient for the induction of apoptosis in endothelial cells, and ER Ca2+ depletion appears to induce apoptosis independently of caspase-12.

KEYWORDS Apoptosis; Calcium; Caspase-12; Endothelial cells

Time for primary review 32 days


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