Redox regulation of platelet function and thrombosis

Platelets are well-known players in several cardiovascular diseases such as

atherosclerosis and venous thrombosis. There are increasing evidence demonstrating

that reactive oxygen species (ROS) is generated within activated platelets. NADPH

oxidase (NOX) is a major source of ROS generation in platelets. Ligand binding to

platelet receptor glycoprotein VI (GPVI) stimulates intracellular ROS generation

consisting of a Syk-independent production involving NOX activation and a following

Syk-dependent generation. In addition to GPVI, stimulation of platelet thrombin

receptors (protease-activated receptors, PARs) can also trigger NOX-derived ROS

production. Our recent study found that mitochondria-derived ROS production can be

induced by engagement of thrombin receptors but not by GPVI, indicating that

mitochondria are another source of PARs-dependent ROS generation apart from NOX.

However, mitochondria are not involved in GPVI-dependent ROS generation. Once

generated, the intracellular ROS are also involved in modulating platelet function and

thrombus formation, therefore, the site-specific targeting of ROS production or

clearance of excess ROS within platelets is a potential intervention and treatment option

for thrombotic events. In this review, we will summarize the signaling pathways

involving regulation of platelet ROS production and their role in platelet function and

thrombosis, with a focus on GPVI and PARs-dependent platelet responses.