Prenylcysteine oxidase 1, an emerging player in atherosclerosis

Abstract

The research into the pathophysiology of atherosclerosis has considerably increased our understanding of the disease complexity, but still many questions remain unanswered, both mechanistically and pharmacologically. Here, we provided evidence that the pro-oxidant enzyme Prenylcysteine Oxidase 1 (PCYOX1), in the human atherosclerotic lesions, is both synthesized locally and transported within the subintimal space by proatherogenic lipoproteins accumulating in the arterial wall during atherogenesis. Further, Pcyox1 deficiency in Apoe-/- mice retards atheroprogression, is associated with decreased features of lesion vulnerability and lower levels of lipid peroxidation, reduces plasma lipid levels and inflammation. PCYOX1 silencing in vitro affects the cellular proteome by influencing multiple functions related to inflammation, oxidative stress, and platelet adhesion. Collectively, these findings identify the pro-oxidant enzyme PCYOX1 as an emerging player in atherogenesis and, therefore, understanding the biology and mechanisms of all functions of this unique enzyme is likely to provide additional therapeutic opportunities in addressing atherosclerosis.

Prenylcysteine Oxidase 1 (PCYOX1), a New Player in Thrombosis

“…PCYOX1 has recently emerged as a lipoprotein-associated protein, representing a potential novel member in the panel of oxidant enzymes involved in the pathogenesis of atherosclerosis [ 7 ]. Its biological functions have thus extended from the former findings by Casey’s group who described PCYOX1 as a lysosomal enzyme involved in the catabolism of prenylated proteins [ 9 ].…”

“…PCYOX1 is a flavin adenine dinucleotide (FAD)-dependent thioether oxidase that produces free cysteine, an isoprenoid aldehyde, and a stoichiometric amount of hydrogen peroxide [ 10 ]. Our previous study identified PCYOX1 as a novel member in the panel of oxidant enzymes involved in the pathogenesis of atherothrombosis [ 7 ]. Being a FAD-dependent thioether oxidase distinguishes it from other oxidant enzymes.…”

“…Remarkably, we recently demonstrated that the secretome of Pcyox1 -silenced cells (HepG2 cells) impaired in vitro adhesion of human platelets to both fibrinogen-coated plates and human endothelial cells. Further, the secretome analysis revealed that PCYOX1 is a multifunctional protein potentially involved in a plethora of systems including the regulation of peptidase activity, platelet degranulation, regulation of signal transduction, response to stress, regulation of response to stimulus, inflammatory response, and response to wounding [ 7 ]. We also showed that Pcyox1 −/− /Apoe −/− mice have a significant decrease in plasma activity of PAI-1, the primary physiological inhibitor of fibrinolysis [ 18 ].…”

“…Prenylcysteine Oxidase 1 (PCYOX1) is an enzyme involved in the degradation of prenylated proteins, and in the release of hydrogen peroxide [ 5 , 6 ]. However, experimental and bioinformatics data [ 7 , 8 ] have showed that PCYOX1 might play additional roles beyond its involvement in the metabolism of prenylated proteins.…”

“…In addition, we recently showed that Pcyox1 deficiency retards atheroprogression in Apoe −/− mice, and it is associated with decreased features of lesion vulnerability. Finally, 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.…”