S-nitrosothiols as selective antithrombotic agents - possible mechanisms

Area of Science:

• Biochemistry
• Pharmacology
• Hematology

Background:

• S-nitrosothiols (RSNOs) are investigated for clinical applications, particularly as antithrombotic agents.
• RSNOs exhibit platelet inhibitory effects, suggesting potential therapeutic benefits in thrombosis.
• The precise mechanism underlying RSNOs' platelet selectivity remains unclear.

Purpose of the Study:

• To elucidate the mechanisms of nitric oxide (NO) delivery from RSNOs into cells.
• To explore the role of different cellular pathways in mediating RSNO effects.
• To identify novel antithrombotic actions of RSNOs.

Main Methods:

• Investigated denitrosation by cell surface enzymes.
• Examined the transport of S-nitrosocysteine via the amino acid transporter system-L (L-AT).
• Assessed the regulation of cell surface targets involved in thrombosis by RSNOs.

Main Results:

• Identified cell surface enzyme denitrosation and L-AT as key pathways for NO signaling from RSNOs.
• Observed differences in these pathways between platelets and vascular cells, potentially explaining platelet selectivity.
• Found that RSNOs regulate exofacial targets like protein disulphide isomerase, integrins, and tissue factor.

Conclusions:

• Cellular uptake and denitrosation pathways contribute to the antithrombotic effects of S-nitrosothiols.
• Differences in these pathways may underlie the observed platelet selectivity of RSNOs.
• RSNOs may offer novel antithrombotic strategies by targeting cell surface proteins, potentially without requiring intracellular NO delivery.