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

Abstract

role in atherogenesis, in part because of its effects on macrophage recruitment and retention ( 7,8 ). Initial oxidation of LDL and formation of what is often referred to as "minimally modifi ed" LDL stimulate adjacent endothelial and smooth muscle cells to release monocyte chemotactic protein-1, which facilitates the recruitment of monocytes into the arterial wall. OxLDL itself is chemotactic for monocytes by virtue of its lysophosphatidylcholine content.At high concentrations, oxLDL can be toxic to cultured macrophages and other cells, but at lower concentrations, it has been clearly shown to promote macrophage proliferation and inhibit apoptosis ( 9-15 ). Our group has recently reported that oxLDL inhibits macrophage apoptosis by activating eukaryotic elongation factor-2 (eEF2) kinase (also known as Ca 2+ /calmodulin-dependent kinase III) ( 16 ). eEF2 kinase activation and inhibition of macrophage apoptosis is mediated by an oscillatory increase in intracellular calcium ([Ca 2+ ] i ). However, the signal transduction pathways involved in oxLDL-mediated [Ca 2+ ] i oscillations have not been elucidated. Ca 2+ is a ubiquitous intracellular signal responsible for controlling numerous cellular processes. These processes range from muscle contraction to synaptic transmission and from cellular proliferation to apoptosis ( 17 ). Ca 2+ can relay specifi city in signaling through its high degree of spatial and temporal diversity ( 18 ) Atherosclerosis is a chronic infl ammatory disease of large and medium-sized arteries, and macrophages play a central role in its initiation and progression ( 1, 2 ). The accumulation of macrophages in lesions is due in part to recruitment of monocytes from the bloodstream ( 2 ) and to proliferation of macrophages within atherosclerotic lesions ( 3-6 ). Oxidized LDL (oxLDL) plays an important Abbreviations: BMDM, bone marrow-derived macrophage; [Ca 2+ ] i , intracellular calcium; DPBS, Dulbecco's phosphate-buffered saline; eEF2, eukaryotic elongation factor-2; ER, endoplasmic reticulum; IP 3 R, inositol-1,4,5-triphosphate receptor; LCM, L929 cell conditioned media; lysoPC, lysophosphatidylcholine; MAPK, mitogen-activated protein kinase; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; oxLDL, oxidized low density lipoprotein; PC, phosphatidylcholine; PLC, phospholipase C; PMS, phenazine methosulfate; RyR, ryanodine receptor; S1P, sphingosine-1-phosphate; SCaMPER, sphingolipid Ca 2+ release mediating protein of the endoplasmic reticulum; SERCA, sarco-endoplasmic reticulum ATPase; SK, sphingosine kinase; SKI, sphingosine kinase inhibitor.

oxLDL antibody inhibits MCP‐1 release in monocytes/macrophages by regulating Ca2+/K+ channel flow

“…B). This indicates that oxLDL‐induced Ca 2+ oscillations are only partly dependent on the membrane Ca 2+ channels, which is in accordance with Johnny H. Chen's results showing that not only extracellular Ca 2+ , but also intracellular stores of Ca 2+ account for the oxLDL‐induced [Ca 2+ ]i oscillations .…”

“…oxLDL has been shown to induce an increase in the intracellular calcium concentration ([Ca 2+ ] i ) in bone marrow‐derived macrophages . Here, we tested whether oxLDL influences the calcium influx in RAW264.7 cells.…”

OxLDL up‐regulates microRNA‐29b, leading to epigenetic modifications of MMP‐2/MMP‐9 genes: a novel mechanism for cardiovascular diseases

“…oxLDL is a proatherosclerotic form of lipoprotein that causes an increase of lipid accumulation in the arterial walls, and it can also enhance the expression of inflammatory cytokines and chemotactic factors in numerous cell types of the arterial walls to further exacerbate the atherosclerosis process (20). The proatherogenic effects of oxLDL are also attributed to the activation of several downstream pathways, including the mitogenactivated protein kinase (MAPK) family (21), phosphatidylinositol 3-kinase (22), ROS generation (23), cal-cium oscillation (24), and transcription factors (25). However, the epigenetic modification regulated by oxLDL in the vessel wall has barely been explored.…”

Regulation of Mammalian Physiology, Development, and Disease by the Sphingosine 1-Phosphate and Lysophosphatidic Acid Receptors

“…Although activation of some LPAR and S1PR can lead to intracellular Ca 2+ mobilization, intracellular LPA or S1P are capable of eliciting Ca 2+ flux via store-operated or non-store-operated Ca 2+ entry channels in diverse cell types, such as neutrophils, mast cells, macrophages, vascular smooth muscle cells, and pulmonary endothelial cells 46,171,172,417-420 . Whether such effects are direct signaling function of the LPs on channel proteins or indirectly through membrane effects is not known.…”