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Peripheral Blood Cell Gene Expression Profiling in Patients with Coronary Artery Disease (Homo sapiens)

ABSTRACT: Expression profiling of peripheral blood mononuclear cells isolated from patients piror to undergoing cardiac catheterization Disease: NonStenotic: 17-0711, 17-0889, 17-0920, 17-0810, 17-0985, 17-0948, 17-0933, 17-0929, 17-0828, 17-0813, 17-1068, 17-0842, 17-0967, 17-0750 Disease: Stentotic: 17-0736, 17-0727, 17-0915, 17-0913, 17-0866, 17-1043, 17-1037, 17-0994, 17-0924, 17-0921, 17-0917, 17-0916, 17-0808, 17-0758, 17-0963, 17-0958, 17-0951, 17-0822, 17-0815, 17-1089, 17-1083, 17-1077, 17-0954, 17-1086, 17-1057, 17-0748, 17-0722 biological repeat: 17-0711, 17-0889, 17-0920, 17-0810, 17-0985, 17-0948, 17-0933, 17-0929, 17-0828, 17-0813, 17-1068, 17-0842, 17-0967, 17-0750 biological repeat: 17-0736, 17-0727, 17-0915, 17-0913, 17-0866, 17-1043, 17-1037, 17-0994, 17-0924, 17-0921, 17-0917, 17-0916, 17-0808, 17-0758, 17-0963, 17-0958, 17-0951, 17-0822, 17-0815, 17-1089, 17-1083, 17-1077, 17-0954, 17-1086, 17-1057, 17-0748, 17-0722 Keywords: disease state analysis

ORGANISM(S): Homo sapiens

PROVIDER: GSE10195 | GEO | 2008/10/08

SECONDARY ACCESSION(S): PRJNA108309

REPOSITORIES: GEO

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Project description:A synthetic analog of sphingosine named FTY720 (Fingolimod), phosphorylated by sphingosine kinase-2, interacts with sphingosine-1-phosphate (S1P) receptors expressed on various cells. FTY720 suppresses the disease activity of multiple sclerosis (MS) chiefly by inhibiting S1P-dependent egress of autoreactive T lymphocytes from secondary lymphoid organs, and possibly by exerting anti-inflammmatory and neuroprotective effects directly on brain cells. However, at present, biological effects of FTY720 on human microglia are largely unknown. We studied FTY720-mediated apoptosis of a human microglia cell line HMO6. The exposure of HMO6 cells to non-phosphorylated FTY720 (FTY720-non-P) induced apoptosis in a dose-dependent manner with IC50 of 10.6±2.0 microM, accompanied by the cleavage of caspase-7 and caspase-3 but not of caspase-9. The apoptosis was inhibited by Z-DQMD-FMK, a caspase-3 inhibitor, but not by Pertussis toxin, a Gi protein inhibitor, suramin, a S1P3/S1P5 inhibitor, or W123, a S1P1 competitive antagonist, although HMO6 expressed S1P1, S1P2, and S1P3. Furthermore, both phosphorylated FTY720 (FTY720-P) and SEW2871, a S1P1 selective agonist did not induce apoptosis of HMO6. Genome-wide gene expression profiling and molecular network analysis indicated activation of transcriptional regulation by sterol regulatory element-binding protein (SREBP) in FTY720-non-P-treated HMO6 cells. Western blot verified activation of SREBP2 in these cells, and apoptosis was enhanced by pretreatment with simvastatin, an activator of SREBP2, and by overexpression of the N-terminal fragment of SREBP2. These observations suggest that FTY720-non-P-induced apoptosis of HMO6 human microglia is independent of S1P receptor binding, and positively regulated by the SREBP2-dependent proapoptotic signaling pathway. The HMO6 cell line was established by immortalizing cultured microglia isolated from human embryonic telencephalon tissues with a retroviral vector PASK1.2 encoding v-myc oncogene (Nagai et al. Neurobiol. Dis. 8: 1057-1068, 2001). HMO6 cells express the markers of the microglia/macrophage lineage cells, including CD11b, CD68, CD86, HLA-ABC, HLA-DR, and ricinus communis agglutinin lectin-1 (RCA), serving as a model of human microglia both in vitro and in vivo. The cells were exposed for 2 hours to 10 microM FTY720-non-P dissolved in dimethyl sulfoxide (DMSO) or ethanol or exposed to the vehicle.

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Peripheral Blood Cell Gene Expression Profiling in Patients with Coronary Artery Disease (Homo sapiens)

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