Arterial thrombotic diseases, including coronary/peripheral artery diseases and stroke, are the number one killer in the U.S. Underlying these pathologies is increased platelet activity. Mounting evidence indicates that oxidation or reduction of allosteric disulfide bonds induces a conformational change(s) in plasma proteins and cell surface molecules and alters their functions. Thiol isomerases, such as protein disulfide isomerase (PDI), are responsible for modifying allosteric disulfide bonds. We have demonstrated that platelet-released PDI directly interacts with cell surface molecules, such as β3 integrin and glycoprotein Ibα (GPIbα), during cell activation and promotes platelet adhesive function in arterial thrombosis and thromboinflammation (Kim et al. Blood 2013; Li et al. Circulation 2019). We are identifying platelet surface receptors whose function is regulated by thiol isomerases and how the activities of PDI and other thiol isomerases are controlled in thrombosis.
Anucleate platelets can synthesize proteins using mRNAs and microRNAs under disease conditions. Intriguingly, platelets contain transcriptional regulators. We have demonstrated that the mRNA and protein of downstream regulatory element antagonist modulator (DREAM, a transcriptional repressor) are present in platelets and that platelet DREAM promotes the activity of phosphoinositide-3-kinase during platelet activation and arterial thrombosis (Kim et al. Blood 2017). These results indicate the possibility of non-transcriptional roles of transcriptional regulators in platelet function. We are identifying the novel signaling pathways modulated by transcription factors and repressors that may affect platelet function in arterial thrombosis.