title: Insulin inhibits apoptosis of macrophage cell line, THP-1 cells, via phosphatidylinositol-3-kinase-dependent pathway.
abstract: Hyperinsulinemia has recently been reported as a risk factor for atherosclerotic diseases such as coronary heart disease; however, its precise mechanism is not well understood. To elucidate the role of insulin in the development of atherogenesis, we have investigated the effect of insulin on cell survival in macrophages, which are known to be important in the atherosclerotic process. Apoptosis was induced in macrophage cell lines derived from human monocytes or murine macrophages by serum starvation. Insulin administration retarded macrophage apoptosis by means of DNA laddering, dimethylthiazol diphenyltetrazolium bromide assay, and annexin V binding assay. Insulin also enhanced mRNA expression and protein production of the antiapoptotic Bcl-XL gene in a dose-dependent manner within the range of physiological concentrations. In the exploration of the signaling pathway involved in these antiapoptotic effects of insulin, pretreatment of cells with a specific inhibitor of phosphatidylinositol-3-kinase significantly suppressed insulin-mediated cell survival and insulin-induced Bcl-XL expression in macrophages. These data indicate that the survival effect of insulin on the apoptosis of macrophages is associated with the upregulation of Bcl-XL expression, and it may be mediated through the phosphatidylinositol-3-kinase signaling pathway. These mechanisms could be involved in the possible role of insulin in the development of atherosclerosis.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan.
authors.forename: Kaoruko Tada
authors.initials: KT
authors.lastname: Iida
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suzuki
authors.forename: Hirohito
authors.initials: H
authors.lastname: Sone
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimano
authors.forename: Hideo
authors.initials: H
authors.lastname: Toyoshima
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yatoh
authors.forename: Tomoichiro
authors.initials: T
authors.lastname: Asano
authors.forename: Yukichi
authors.initials: Y
authors.lastname: Okuda
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Yamada
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002467:Cell Nucleus / Q000648:ultrastructure; D053938:DNA Fragmentation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D000077191:Wortmannin; D051020:bcl-X Protein
chemical_list: D000730:Androstadienes; D004791:Enzyme Inhibitors; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D011972:Receptor, Insulin; D000077191:Wortmannin; D051020:bcl-X Protein; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse