Redistribution of intracellular calcium and its effect on apoptosis in macrophages: Induction by oxidized LDL.

Abstract

Calcium signaling, as a key to early step of the elementary intracellular events, has been implicated in controlling the development of atherosclerosis. We have shown previously that oxidized low density lipoprotein OxLDL-induced spatiotemporal increases of intracellular free calcium ([Ca(2+)](i)) in the early formation of macrophage foam cells. Here, we evaluated how spatiotemporal redistribution of intracellular calcium occurs and would affect OxLDL-induced apoptosis. Confocal laser scanning microscopy and flow cytometry showed the time-dependent increase of mitochondrial Ca(2+) ([Ca(2+)](m)) in acute and chronic exposure of U937-derived macrophages to OxLDL (100 microg/ml). Independent of the presence or absence of external Ca(2+), OxLDL-induced a peak of [Ca(2+)](m) in acute exposure, whose amplitude in the absence of extracellular Ca(2+) was obviously lower than the presence of extracellular Ca(2+). In addition, the thapsigargin-mediated increase of [Ca(2+)](i), through endoplasmic reticulum (ER) Ca(2+) pump depletion, was obviously reduced by 1-h pretreatment of OxLDL. OxLDL also caused a time-dependent opening of mitochondrial permeability transition pores (PTPs). EGTA/AM, an intracellular Ca(2+) chelator, significantly reduced OxLDL-induced apoptosis and failed to prevent OxLDL-induced necrosis at 6h. In contrast to control cells, chelation of cytosolic Ca(2+) by EGTA/AM at 6h did not completely reverse OxLDL-induced apoptosis. OxLDL stimulated depolarization of mitochondrial membrane potential (Deltapsi) in time-dependent manner. Our data demonstrated that OxLDL-induced spatiotemporal Ca(2+) redistribution in appropriate organelles and mediated Ca(2+)-dependent apoptosis in relation to depolarization of Deltapsi. These findings suggested that manipulation of the intracellular calcium balance may be a useful strategy to limit the loss of macrophages in early atherosclerosis.

• Authors: Tongle Deng, Le Zhang, Yakun Ge, Min Lu, Xiaoxiang Zheng
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 63 Issue 4 Pg. 267-74 (May 2009) ISSN: 1950-6007 [Electronic] France
• PMID: 18602792 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Culture Media, Serum-Free
• Lipoproteins, LDL
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• oxidized low density lipoprotein
• Egtazic Acid
• Thapsigargin
• EGTA acetoxymethyl ester
• Tetradecanoylphorbol Acetate

Topics

• Apoptosis (drug effects)
• Calcium Signaling (drug effects)
• Cell Differentiation (drug effects)
• Culture Media, Serum-Free (pharmacology)
• Egtazic Acid (analogs & derivatives, pharmacology)
• Humans
• Lipoproteins, LDL (pharmacology)
• Macrophages (cytology, drug effects)
• Membrane Potentials (drug effects)
• Mitochondria (drug effects)
• Mitochondrial Membrane Transport Proteins (drug effects)
• Mitochondrial Membranes (drug effects, physiology)
• Mitochondrial Permeability Transition Pore
• Necrosis
• Tetradecanoylphorbol Acetate (pharmacology)
• Thapsigargin (pharmacology)
• U937 Cells (cytology, drug effects)