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http://purl.uniprot.org/citations/21628952http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/21628952http://www.w3.org/2000/01/rdf-schema#comment"

Aim

Thrombin induces vascular responses including the promotion of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) protein expression, which is modulated by small GTPases RhoA and Rac1, Ca(2+) signaling and reactive oxygen species (ROS). Recent studies have shown that membrane type 1 matrix metalloproteinase (MT1-MMP) functions not only as a protease but also as a signaling molecule. In this study, we hypothesized that MT1-MMP may mediate RhoA and Rac1 activation and their downstream events in thrombin-stimulated endothelial cells.

Methods

We used cultured human aortic endothelial cells (HAECs). MT1-MMP was silenced by small interfering RNA (siRNA). RhoA was inhibited by C3 exoenzyme, whereas adenovirus-mediated gene transfection of dominant negative RhoA and Rac1 was used for the inhibition of RhoA and Rac1. RhoA and Rac1 activation was determined by pull-down assays. Intracellular Ca(2+) concentrations ([Ca(2+)](i)) were fluorescently measured by fura-2 assay. NADPH oxidase activity was determined by lucigenin-enhanced chemiluminescence.

Results

Inhibition of RhoA attenuated thrombin-triggered [Ca(2+)](i) increase and TF and PAI-1 expression in HAECs, whereas thrombin-triggered ROS generation and TF and PAI-1 expression were blocked by inhibition of Rac1. Silencing of MT1-MMP attenuated thrombin-triggered RhoA and Rac1 activation, resulting in the attenuation of downstream events including Ca(2+) signaling, NADPH oxidase activity, ROS generation, and TF and PAI-1 expression.

Conclusions

The present study shows that MT1-MMP mediates the RhoA/Ca(2+) and Rac1/NADPH oxidase-dependent signaling pathways in thrombin-induced vascular responses."xsd:string
http://purl.uniprot.org/citations/21628952http://purl.org/dc/terms/identifier"doi:10.5551/jat.6783"xsd:string
http://purl.uniprot.org/citations/21628952http://purl.uniprot.org/core/author"Ishibashi T."xsd:string
http://purl.uniprot.org/citations/21628952http://purl.uniprot.org/core/author"Inoue N."xsd:string
http://purl.uniprot.org/citations/21628952http://purl.uniprot.org/core/author"Sugimoto K."xsd:string
http://purl.uniprot.org/citations/21628952http://purl.uniprot.org/core/author"Ando K."xsd:string
http://purl.uniprot.org/citations/21628952http://purl.uniprot.org/core/author"Hu C."xsd:string
http://purl.uniprot.org/citations/21628952http://purl.uniprot.org/core/author"Okamoto Y."xsd:string
http://purl.uniprot.org/citations/21628952http://purl.uniprot.org/core/author"Takeishi Y."xsd:string
http://purl.uniprot.org/citations/21628952http://purl.uniprot.org/core/author"Takuwa Y."xsd:string
http://purl.uniprot.org/citations/21628952http://purl.uniprot.org/core/author"Ohkawara H."xsd:string
http://purl.uniprot.org/citations/21628952http://purl.uniprot.org/core/author"Uekita H."xsd:string
http://purl.uniprot.org/citations/21628952http://purl.uniprot.org/core/date"2011"xsd:gYear
http://purl.uniprot.org/citations/21628952http://purl.uniprot.org/core/name"J Atheroscler Thromb"xsd:string
http://purl.uniprot.org/citations/21628952http://purl.uniprot.org/core/pages"762-773"xsd:string
http://purl.uniprot.org/citations/21628952http://purl.uniprot.org/core/title"Crucial role of membrane type 1 matrix metalloproteinase (MT1- MMP) in RhoA/Rac1-dependent signaling pathways in thrombin- stimulated endothelial cells."xsd:string
http://purl.uniprot.org/citations/21628952http://purl.uniprot.org/core/volume"18"xsd:string
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