Abstract
Prenylcysteine Oxidase 1 (PCYOX1) is an enzyme involved in the degradation of prenylated proteins. It is expressed in different tissues including vascular and blood cells. We recently showed that the secretome from Pcyox1-silenced cells reduced platelet adhesion both to fibrinogen and endothelial cells, suggesting a potential contribution of PCYOX1 into thrombus formation. Here, we show that in vivo thrombus formation after FeCl3 injury of the carotid artery was delayed in Pcyox1−/− mice, which were also protected from collagen/epinephrine induced thromboembolism. The Pcyox1−/− mice displayed normal blood cells count, vascular procoagulant activity and plasma fibrinogen levels. Deletion of Pcyox1 reduced the platelet/leukocyte aggregates in whole blood, as well as the platelet aggregation, the alpha granules release, and the αIIbβ3 integrin activation in platelet-rich plasma, in response to adenosine diphosphate (ADP) or thrombin receptor agonist peptide (TRAP). Washed platelets from the Pcyox1−/− and WT animals showed similar phosphorylation pathway activation, adhesion ability and aggregation. The presence of Pcyox1−/− plasma impaired agonist-induced WT platelet aggregation. Our findings show that the absence of PCYOX1 results in platelet hypo-reactivity and impaired arterial thrombosis, and indicates that PCYOX1 could be a novel target for antithrombotic drugs.
Highlights
Despite the great advances made in the treatment of coronary artery disease (CAD), it is still the largest cause of death in industrialised and non-industrialised countries
Data are expressed as mean ± standard error of the mean (SEM). n: wild type (WT) = 16 mice and Prenylcysteine Oxidase 1 knock-out (Pcyox1−/−) = 10 mice
We found that the protective effect of Pcyox1 deletion on thrombosis seems to be not related to alterations in the vascular thrombogenicity, as suggested by the lack of difference in tissue factor (TF) procoagulant activity between Pcyox1−/− and WT mice (Figure 2, p = 0.847)
Summary
Despite the great advances made in the treatment of coronary artery disease (CAD), it is still the largest cause of death in industrialised and non-industrialised countries. Platelets are actively involved in thrombosis and in addition, by interacting with leukocytes, they participate in the initiation and progression of atherosclerotic plaque [2] Another important process is related to the reactive oxygen species (ROS), that by increasing the oxidative stress, induce the oxidation of lipoproteins, the activation of tissue factor (TF), the primary initiator of coagulation cascade, and enhance endothelial dysfunction and platelet hyper-reactivity. The secretome from Pcyox1-silenced cells reduced platelet adhesion both to fibrinogen and endothelial cells [7], suggesting a potential contribution of PCYOX1 into thrombus formation. Given these premises, taking advantage of the Pcyox gene knockout (Pcyox1−/−) C57BL/6J mice, here we investigated the effect of PCYOX1 deletion on thrombosis
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