BMP-7 induces TF expression in human monocytes by increasing F3 transcriptional activity. Issue 2 (February 2015)

• Record Type: Journal Article
• Authors: Sovershaev, T.A.; Egorina, E.M.; Unruh, D.; Bogdanov, V.Y.; Hansen, J.B.; Sovershaev, M.A.
• Is Part Of: Thrombosis research. Volume 135:Issue 2(2015)
• Page Start: 398
• Page End: 403
• Publication Date: 2015-02
• Subjects: Thrombosis -- Periodicals; 616.135
• DOI: 10.1016/j.thromres.2014.11.031
• Languages: English
• ISSNs: 0049-3848

Abstract

<abstract abstract-type="author" id="ab0005"> <title id="st0005">Abstract</title> <sec> <title id="st0010">Background</title> <p id="sp0005">Bone morphogenetic protein (BMP)-7, a major regulator of bone metabolism, inhibits ectopic calcification in atherosclerotic plaques. We have recently reported that BMP-7 is also a potent inducer of tissue factor (TF) in human mononuclear cells (MNCs). While nuclear factor kappa beta (NF-kB) and activation protein-1 (AP-1) are the transcription factors essential for inducible expression of human TF gene (<italic>F3</italic>), the mechanisms responsible for TF induction by BMP-7 are not known.</p> </sec> <sec> <title id="st0015">Objective</title> <p id="sp0010">To elucidate the molecular mechanisms governing BMP-7-triggered TF expression in human MNCs.</p> </sec> <sec> <title id="st0020">Methods</title> <p id="sp0015">Human blood monocytes were stimulated with BMP-7 and western blotting, qRT-PCR, and flow cytometry studies were carried out to assess <italic>F3</italic> expression; promoter studies were also performed using a panel of reporter constructs. Procoagulant TF activity was measured using a validated FXa generation assay. The significance of NF-kB transcriptional activity was verified via pharmacological inhibition.</p> </sec> <sec> <title id="st0025">Results</title> <p id="sp0020">BMP-7 increased TF protein levels, procoagulant activity, surface presentation, and TF mRNA expression. This increase was accompanied by activation of NF-kB as evidenced by reduced IkB-α levels and elevated transcriptional activity of an NF-kB-sensitive reporter in transfected MNCs. Although treatment with BMP-7 also led to a strong phosphorylation of c-Jun, activation of AP-1 alone was not sufficient to induce TF expression: JSH-23, a potent and specific NF-kB inhibitor, completely blocked BMP-7-induced TF expression.</p> </sec> <sec> <title id="st0030">Conclusions</title> <p id="sp0025">We report that BMP-7-dependent activation of TF in human MNCs is mediated via increased activity of NF-kB, leading to enhanced <italic>F3</italic> transcription in human MNCs.</p> </sec> </abstract>