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Comprehensive Analysis of Procoagulant Platelets Exhibiting Features of Necrosis, Apoptosis and Platelet Activation
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Proteasome proteolysis supports stimulated platelet function and thrombosis
Nilaksh Gupta1, Wei Li, Belinda Willard
1From the Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland, OH (N.G., W.L., B.W., R.L.S., T.M.M.); and Department of Biological Geological and Environmental Sciences, Cleveland State University, Cleveland, OH (N.G., T.M.M.).
Arteriosclerosis, Thrombosis, and Vascular Biology
|November 2, 2013
Summary
Platelets possess a ubiquitin/proteasome system that regulates cytoskeletal proteins. Inhibiting this system impacts platelet function and reduces thrombosis, suggesting a novel therapeutic target.
Area of Science:
- Hematology
- Cell Biology
- Biochemistry
Background:
- Proteasome inhibitors are used for hematologic cancers and reduce thrombosis.
- The role of the proteasome in platelet activation and function is largely unknown.
Purpose of the Study:
- To investigate the presence and function of the ubiquitin/proteasome system in platelets.
- To determine the effect of proteasome inhibition on platelet activation, aggregation, and thrombosis.
Main Methods:
- Assessed proteasome activity in platelets using specific inhibitors (MG132, bortezomib).
- Analyzed ubiquitination of platelet proteins via mass spectrometry.
- Evaluated thrombosis in vivo using a mouse carotid artery injury model.
- Measured platelet aggregation, spreading, and microparticle shedding ex vivo.
Main Results:
- Platelets exhibit proteasome activity inhibited by MG132 and bortezomib.
- A functional ubiquitination system modifies platelet proteins.
- Proteasome inhibition suppressed thrombus formation in vivo and ex vivo.
- Inhibition reduced platelet aggregation, spreading, and microparticle shedding.
- Ubiquitination of cytoskeletal proteins Filamin A and Talin-1 increased upon proteasome inhibition.
Conclusions:
- Platelets possess a ubiquitin/proteasome system crucial for cytoskeletal protein modification.
- This system regulates platelet interactions, contributing to thrombosis.
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