PMID- 21820697 OWN - NLM STAT- MEDLINE DCOM- 20120611 LR - 20111128 IS - 1879-2472 (Electronic) IS - 0049-3848 (Linking) VI - 128 IP - 6 DP - 2011 Dec TI - Increased expression of TF in BMP-7-treated human mononuclear cells depends on activation of select MAPK signaling pathways. PG - e154-9 LID - 10.1016/j.thromres.2011.07.027 [doi] AB - Bone morphogenetic protein (BMP)-7 regulates atherosclerotic plaque calcification, and it contributes to increased thrombogenicity of lipid-rich lesions by enhancement of TF expression in monocytes/macrophages by unknown mechanism. Since Erk1/2, JNK and p38 mitogen activated protein kinases (MAPKs) regulate TF expression, we studied involvement of MAPK pathways in BMP-7-induced activation of TF in human mononuclear cells (MNCs). Whole blood from healthy volunteers was treated with BMP-7, MNCs were isolated, and TF expression was assessed by western blot (WB) and In-Cell Western assay. Phosphorylation and nuclear translocation of Smad1/5/8 in response to BMP-7 stimulation of MNCs was evaluated by WB and confocal microscopy. Activation of MAPKs was judged by measuring the levels of phoshorylated Erk1/2, JNK, and p38 in the lysates of MNCs. The impact of Erk1/2 and p38 activation was studied by use of PD98059 and SB203580 inhibitors, respectively. Stimulation of whole blood with BMP-7 increased the levels of TF in the lysates of MNCs by 7-fold as compared to 12-fold after LPS stimulation. It was followed by elevation in TF fuctional activity. It was accompanied by elevated levels of phosphorylated Smad 1/5/8 and nuclear translocation of Smad1/5/8 proteins. Treatment of whole blood with BMP-7 led to a phosphorylation of Erk1/2, JNK and p38 MAPKs. BMP-7-induced TF expression was partially inhibited by Erk1/2 inhibitor, whereas TF expression was completely abolished by p38 inhibitor. BMP-7-dependent activation of TF in human MNCs by BMP-7 is accompanied by activation of canonic Smad1/5/8 signaling pathway and depends on activation of Erk1/2 and p38. CI - Copyright (c) 2011 Elsevier Ltd. All rights reserved. FAU - Sovershaev, M A AU - Sovershaev MA AD - Hematological Research Group, Department of Clinical Medicine, the Faculty of Health Sciences, University of Tromso, N-9037, Tromso, Norway. mikhail.sovershaev@uit.no FAU - Egorina, E M AU - Egorina EM FAU - Sovershaev, T A AU - Sovershaev TA FAU - Svensson, B AU - Svensson B FAU - Hansen, J B AU - Hansen JB LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20110806 PL - United States TA - Thromb Res JT - Thrombosis research JID - 0326377 RN - 0 (Bone Morphogenetic Protein 7) RN - 0 (Smad Proteins) RN - 76057-06-2 (Transforming Growth Factors) RN - 9035-58-9 (Thromboplastin) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - EC 2.7.12.2 (MAP Kinase Kinase 4) SB - IM MH - Bone Morphogenetic Protein 7/*pharmacology MH - Cell Differentiation MH - Female MH - Humans MH - MAP Kinase Kinase 4/metabolism MH - MAP Kinase Signaling System/*drug effects MH - Male MH - Mitogen-Activated Protein Kinase 1/metabolism MH - Mitogen-Activated Protein Kinase 3/metabolism MH - Monocytes/*drug effects/enzymology/*metabolism MH - Phosphorylation MH - Smad Proteins/*metabolism MH - Thromboplastin/*biosynthesis MH - Transforming Growth Factors/metabolism MH - p38 Mitogen-Activated Protein Kinases/metabolism EDAT- 2011/08/09 06:00 MHDA- 2012/06/12 06:00 CRDT- 2011/08/09 06:00 PHST- 2011/04/16 00:00 [received] PHST- 2011/07/03 00:00 [revised] PHST- 2011/07/13 00:00 [accepted] PHST- 2011/08/09 06:00 [entrez] PHST- 2011/08/09 06:00 [pubmed] PHST- 2012/06/12 06:00 [medline] AID - S0049-3848(11)00373-2 [pii] AID - 10.1016/j.thromres.2011.07.027 [doi] PST - ppublish SO - Thromb Res. 2011 Dec;128(6):e154-9. doi: 10.1016/j.thromres.2011.07.027. Epub 2011 Aug 6.