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.
Highlights
Matrix metalloproteinase (MMP) proteins, a large family of Zndependent endopeptidases, are responsible for degrading a variety of extracellular matrix (ECM) components and for modulating the bioactivity of transmembrane receptors and soluble factors [1,2]
Our previous study provides evidence that a lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1)-Membrane type 1– matrix metalloproteinase (MT1-MMP) axis plays a crucial role in RhoA and Rac1 activation signaling pathways in endothelial dysfunction induced by oxidized lowdensity lipoprotein, suggesting that this axis may be a promising target for treating endothelial dysfunction [10]
tissue factor (TF) antigen levels were increased in a dose-dependent manner up to 10 ng/mL tumor necrosis factor (TNF)-a, whereas TM antigen levels were decreased in TNF-a stimulated endothelial cells (ECs) (Figures 1A and B)
Summary
Matrix metalloproteinase (MMP) proteins, a large family of Zndependent endopeptidases, are responsible for degrading a variety of extracellular matrix (ECM) components and for modulating the bioactivity of transmembrane receptors and soluble factors [1,2]. Our previous study provides evidence that a lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1)-MT1-MMP axis plays a crucial role in RhoA and Rac activation signaling pathways in endothelial dysfunction induced by oxidized lowdensity lipoprotein (ox-LDL), suggesting that this axis may be a promising target for treating endothelial dysfunction [10]. We reported that MT1-MMP controls thrombintriggered RhoA and Rac activation, resulting in downstream events including Ca2+ signaling, reactive oxygen species generation, expressions of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) in human aortic endothelial cells (ECs) [11]
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