A Novel mRNA Binding Protein Complex Promotes Localized Plasminogen Activator Inhibitor-1 Accumulation at the Myoendothelial Junction

Abstract
Objective—Plasminogen activator inhibitor-1 (PAI-1) has previously been shown to be key to the formation of myoendothelial junctions (MEJs) in normal and pathological states (eg, obesity). We therefore sought to identify the mechanism whereby PAI-1 could be selectively accumulated at the MEJ.
Methods and Results—We identified PAI-1 protein enrichment at the MEJ in obese mice and in response to tumor necrosis factor (TNF-α) with a vascular cell coculture. However, PAI-1 mRNA was also found at the MEJ and transfection with a PAI-1–GFP with TNF-α did not demonstrate trafficking of the protein to the MEJ. We therefore hypothesized the PAI-1 mRNA was being locally translated and identified serpine binding protein-1, which stabilizes PAI-1 mRNA, as being enriched in obese mice and after treatment with TNF-α, whereas Staufen, which degrades PAI-1 mRNA, was absent in obese mice and after TNF-α application. We identified nicotinamide phosphoribosyl transferase as a serpine binding protein-1 binding partner with a functional τ-like microtubule binding domain. Application of peptides against the microtubule binding domain significantly decreased the number of MEJs and the amount of PAI-1 at the MEJ.
Conclusion—We conclude that PAI-1 can be locally translated at the MEJ due to a unique mRNA binding protein complex.
- Received October 28, 2011.
- Accepted February 20, 2012.
- © 2012 American Heart Association, Inc.
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- A Novel mRNA Binding Protein Complex Promotes Localized Plasminogen Activator Inhibitor-1 Accumulation at the Myoendothelial JunctionKatherine R. Heberlein, Jenny Han, Adam C. Straub, Angela K. Best, Christoph Kaun, Johann Wojta and Brant E. IsaksonArteriosclerosis, Thrombosis, and Vascular Biology. 2012;ATVBAHA.112.246371, originally published March 1, 2012https://doi.org/10.1161/ATVBAHA.112.246371
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- A Novel mRNA Binding Protein Complex Promotes Localized Plasminogen Activator Inhibitor-1 Accumulation at the Myoendothelial JunctionKatherine R. Heberlein, Jenny Han, Adam C. Straub, Angela K. Best, Christoph Kaun, Johann Wojta and Brant E. IsaksonArteriosclerosis, Thrombosis, and Vascular Biology. 2012;ATVBAHA.112.246371, originally published March 1, 2012https://doi.org/10.1161/ATVBAHA.112.246371