Protein disulfide isomerase regulation by nitric oxide maintains vascular quiescence and controls thrombus formation. (12th October 2018)

• Record Type: Journal Article
• Authors: Bekendam, R. H.; Iyu, D.; Passam, F.; Stopa, J. D.; De Ceunynck, K.; Muse, O.; Bendapudi, P. K.; Garnier, C. L.; Gopal, S.; Crescence, L.; Chiu, J.; Furie, B.; Panicot‐Dubois, L.; Hogg, P. J.; Dubois, C.; Flaumenhaft, R.
• Is Part Of: Journal of thrombosis and haemostasis. Volume 16:Number 11(2018)
• Page Start: 2322
• Page End: 2335
• Publication Date: 2018-10-12
• Subjects: nitric oxide -- platelets -- protein disulfide isomerase -- S‐nitrosylation -- thrombosis; Thrombosis -- Periodicals; Hemostasis -- Periodicals; Blood coagulation disorders -- Periodicals; 616.1
• DOI: 10.1111/jth.14291
• Languages: English
• ISSNs: 1538-7933

Abstract

Abstract : Essentials Nitric oxide synthesis controls protein disulfide isomerase (PDI) function. Nitric oxide (NO) modulation of PDI controls endothelial thrombogenicity. S‐nitrosylated PDI inhibits platelet function and thrombosis. Nitric oxide maintains vascular quiescence in part through inhibition of PDI. Summary: Background: Protein disulfide isomerase (PDI) plays an essential role in thrombus formation, and PDI inhibition is being evaluated clinically as a novel anticoagulant strategy. However, little is known about the regulation of PDI in the vasculature. Thiols within the catalytic motif of PDI are essential for its role in thrombosis. These same thiols bind nitric oxide (NO), which is a potent regulator of vessel function. To determine whether regulation of PDI represents a mechanism by which NO controls vascular quiescence, we evaluated the effect of NO on PDI function in endothelial cells and platelets, and thrombus formation in vivo . Aim: To assess the effect of S‐nitrosylation on the regulation of PDI and other thiol isomerases in the vasculature. Methods and results: The role of endogenous NO in PDI activity was evaluated by incubating endothelium with an NO scavenger, which resulted in exposure of free thiols, increased thiol isomerase activity, and enhanced thrombin generation on the cell membrane. Conversely, exposure of endothelium to NO + carriers or elevation of endogenous NO levels by induction of NO synthesis resulted in S‐nitrosylation of PDI and decreased surface thiol reductase activity. S‐nitrosylation of platelet PDI inhibited its reductase activity, and S‐nitrosylated PDI interfered with platelet aggregation, α‐granule release, and thrombin generation on platelets. S‐nitrosylated PDI also blocked laser‐induced thrombus formation when infused into mice. S‐nitrosylated ERp5 and ERp57 were found to have similar inhibitory activity. Conclusions: These studies identify NO as a critical regulator of vascular PDI, and show that regulation of PDI function is an important mechanism by which NO maintains vascular quiescence.