Abstract
N-acetylcysteine (NAC) is able to break down protein disulfides, generating free thiols. This mechanism occurs on mixed disulfides of albumin (HSA) to form mercaptoalbumin (HMA), the main antioxidant species in the plasma. Circulating HSA exists in two main forms: the reduced form (HMA), and the oxidized forms, whose predominant modification is cystenylation (HSA-Cys). Increased levels of oxidized HSA have been detected in several diseases associated with oxidative stress. This study showed that NAC inhibits platelet aggregation by restoring HMA. In addition, the regeneration of HMA by NAC inhibits platelet functions such as intracellular calcium mobilization, reactive oxygen species generation, arachidonic acid metabolites synthesis, and adhesion to the collagen matrix. In our conditions, the exposure of platelets to NAC did not increase GSH levels. However, the inhibition of platelet aggregation was also detected following treatment of platelet-rich plasma with GSH, which, similarly to NAC, reduced HSA-Cys levels. Furthermore, this study showed that cysteine, another compound able to restore HMA by reducing the HSA-Cys content, inhibited platelet aggregation to a similar extent as NAC. The results obtained in this study suggest a new mechanism by which NAC can modulate platelet activation and suggest its possible use as an antiplatelet drug in conditions associated with oxidative stress.
Highlights
N-acetylcysteine (NAC) is a widely used drug in clinical practice as a mucolytic [1] and detoxifying agent against acetaminophen poisoning [2]
Platelets were stimulated with 0.5 μg/mL collagen, and aggregation was monitored for 6 min
This paper showed that NAC is able to reduce platelet activation through a mechanism recently described, which is based on its disulfide-breaking activity and involves the reduction in HSA-Cys
Summary
N-acetylcysteine (NAC) is a widely used drug in clinical practice as a mucolytic [1] and detoxifying agent against acetaminophen poisoning [2]. Despite the efficacy of NAC being mainly attributed to its antioxidant-dependent ability to generate GSH, all the mechanisms underlying its activity are not yet fully understood in that they may not depend exclusively on GSH replenishment [14,15]. It should be noted, that the bioavailability of NAC is very low because at physiological pH, the carboxyl group loses its proton, becoming negatively charged, reducing the ability of NAC to cross the cell membrane [16].
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