title: Membrane type 1-matrix metalloproteinase/Akt signaling axis modulates TNF-α-induced procoagulant activity and apoptosis in endothelial cells.
abstract: Membrane type 1-matrix metalloproteinase (MT1-MMP) functions as a signaling molecule in addition to a proteolytic enzyme. Our hypothesis was that MT1-MMP cooperates with protein kinase B (Akt) in tumor necrosis factor (TNF)-α-induced signaling pathways of vascular responses, including tissue factor (TF) procoagulant activity and endothelial apoptosis, in cultured human aortic endothelial cells (ECs). TNF-α (10 ng/mL) induced a decrease in Akt phosphorylation within 60 minutes in ECs. A chemical inhibitor of MMP, TIMP-2 and selective small interfering RNA (siRNA)-mediated suppression of MT1-MMP reversed TNF-α-triggered transient decrease of Akt phosphorylation within 60 minutes, suggesting that MT1-MMP may be a key regulator of Akt phosphorylation in TNF-α-stimulated ECs. In the downstream events, TNF-α increased TF antigen and activity, and suppressed the expression of thrombomodulin (TM) antigen. Inhibition of Akt markedly enhanced TNF-α-induced expression of TF antigen and activity, and further reduced the expression of TM antigen. Silencing of MT1-MMP by siRNA also reversed the changed expression of TF and TM induced by TNF-α. Moreover, TNF-α induced apoptosis of ECs through Akt- and forkhead box protein O1 (FoxO1)-dependent signaling pathway and nuclear factor-kB (NF-kB) activation. Knockdown of MT1-MMP by siRNA reversed apoptosis of ECs by inhibiting TNF-α-induced Akt-dependent regulation of FoxO1 in TNF-α-stimulated ECs. Immunoprecipitation demonstrated that TNF-α induced the changes in the associations between the cytoplasmic fraction of MT1-MMP and Akt in ECs. In conclusion, we show new evidence that MT1-MMP/Akt signaling axis is a key modifier for TNF-α-induced signaling pathways for modulation of procoagulant activity and apoptosis of ECs.
authors.affiliation: Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohkawara
authors.affiliation: Department of Cardiovascular Medicine, Ohara General Hospital Medical Center, Fukushima, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ishibashi
authors.affiliation: Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Sugimoto
authors.affiliation: Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.
authors.forename: Kazuei
authors.initials: K
authors.lastname: Ogawa
authors.affiliation: Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.
authors.forename: Yasuchika
authors.initials: Y
authors.lastname: Takeishi
mesh_terms: D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D003029:Coagulants / Q000378:metabolism / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018180:Thrombomodulin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D003029:Coagulants; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D016328:NF-kappa B; D034741:RNA, Small Interfering; C546931:THBD protein, human; D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; D019716:Tissue Inhibitor of Metalloproteinase-2; D013925:Thromboplastin; D051057:Proto-Oncogene Proteins c-akt; D053511:Matrix Metalloproteinase 14