Sphingosine kinase regulates oxidized low density lipoprotein-mediated calcium oscillations and macrophage survival

• Published in: Journal of lipid research 2010-05, Vol.51 (5), p.991-998
• Main Authors: Chen, Johnny H., Riazy, Maziar, Wang, Shih Wei, Dai, Jiazhen Minnie, Duronio, Vincent, Steinbrecher, Urs P.
• Format: Article
• Language: English
• Subjects: Animals; Biological Transport - drug effects; calcium; Calcium - metabolism; Calcium Channel Blockers - pharmacology; Cell Line; Cell Survival - drug effects; Endoplasmic Reticulum - metabolism; Enzyme Activation - drug effects; Extracellular Space - drug effects; Extracellular Space - metabolism; Female; foam cells; Humans; Lipoproteins, LDL - pharmacology; Lysophosphatidylcholines - metabolism; Lysophospholipids - metabolism; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Mice; Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors; Phosphotransferases (Alcohol Group Acceptor) - metabolism; plaque stability; Ryanodine Receptor Calcium Release Channel - metabolism; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; Sphingosine - analogs & derivatives; Sphingosine - metabolism; sphingosine-1-phosphate; Thapsigargin - pharmacology; Type C Phospholipases - antagonists & inhibitors
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M000398

We recently reported that oxidized LDL (oxLDL) induces an oscillatory increase in intracellular calcium ([Ca2+]i) levels in macrophages. Furthermore, we have shown that these [Ca2+]i oscillations mediate oxLDL's ability to inhibit macrophage apoptosis in response to growth factor deprivation. However, the signal transduction pathways by which oxLDL induces [Ca2+]i oscillations have not been elucidated. In this study, we show that these oscillations are mediated in part by intracellular mechanisms, as depleting extracellular Ca2+ did not completely abolish the effect. Inhibiting sarco-endoplasmic reticulum ATPase (SERCA) completely blocked [Ca2+]i oscillations, suggesting a role for Ca2+ reuptake by the ER. The addition of oxLDL resulted in an almost immediate activation of sphingosine kinase (SK), which can increase sphingosine-1-phosphate (S1P) levels by phosphorylating sphingosine. Moreover, S1P was shown to be as effective as oxLDL in blocking macrophage apoptosis and producing [Ca2+]i oscillations. This suggests that the mechanism in which oxLDL generates [Ca2+]i oscillations may be 1) activation of SK, 2) SK-mediated increase in S1P levels, 3) S1P-mediated Ca2+ release from intracellular stores, and 4) SERCA-mediated Ca2+ reuptake back into the ER.