S-nitrosation/Denitrosation in Cardiovascular Pathologies: Facts and Concepts for the Rational Design of S-nitrosothiols
Résumé
Nitric oxide ((NO)-N-center dot) is a physiological mediator of vasorelaxation constitutively synthesized by endothelial nitric oxide synthase. Because (NO)-N-center dot has a short half-life, it is stored by proteins through S-nitrosation reactions. S-nitrosation was recently defined as a post-translational modification of proteins for cellular signalling, as important as glycosylation and phosphorylation. Disulfide forming/isomerizing enzymes like thioredoxin (Trx), protein disulfide isomerase (PDI), which are chaperone proteins, are implicated into transnitrosation reactions, which are the transfer of (NO)-N-center dot from one cysteine residue to another one. Furthermore, Trx has been shown to denitrosate S-nitrosoproteins depending on its redox status. S-nitrosation of Trx on Cys residues apart from active site, under nitrosative or oxidative stresses, enhances its activity, thereby reducing intracellular reactive oxygen species. Trx and PDI have therefore an essential role for cell signalling control which leads, among other actions, to cardio and vasculo-protection. The diminution of either (NO)-N-center dot synthesis or bioavailability is implicated into a large number of cardiovascular pathologies associated to hypoxia or vasoconstriction like, endothelial dysfunction, arterial hypertension and atherosclerosis. In order to mimic the physiological storage of (NO)-N-center dot as S-nitrosothiols, the development of (NO)-N-center dot donors should be based on the covalent S-NO bond. The chemical stabilisation of the S-NO bond and protection against enzymatically active proteins such as PDI//Trx are major points for the design of stable compounds. S-nitrosothiols entrapment in innovative formulations (films, gels, microparticles, nanoparticles) is an emerging field in order to stabilise and protect them, and to deliver (NO)-N-center dot under a sustained release at the targeted site.