Background and Aims

The research into the pathophysiology of atherosclerosis has considerably increased our understanding of the complexity of the disease, but still many questions remain unanswered, and the burden of recurrent cardiovascular events remains unacceptable, despite optimal treatment with contemporary intervention and pharmacologic agents.

Our previous findings that prenylcysteine oxidase 1 (PCYOX1) represents a novel lipoprotein-associated protein, and that lipoproteins can themselves generate the reactive oxygen species H₂O₂ through the action of PCYOX1, prompted us to investigate the biological role of this unique enzyme in the development of atherosclerosis.

Methods

Gene silencing approaches with proteomic and biochemical analysis have been introduced to study PCYOX1 biological functions. In vivo localization of PCYOX1 has been performed in human atherosclerotic lesions and aortic arch of ApoE^-/- mice. A double knockout mouse model (PCYOX1^−/−/apoE^−/− mice) was treated with Western-type diet in order to study atherosclerotic lesion progression and the inflammatory status.

Results

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, improves plasma lipid profile, and reduces inflammation.

Conclusions

Collectively, these findings identify the pro-oxidant enzyme PCYOX1 as a novel player in atherogenesis and, therefore, understanding the biology and mechanisms of all functions of this unique enzyme is likely to provide significant therapeutic opportunities in addressing atherosclerosis

Background and Aims

The research into the pathophysiology of atherosclerosis has considerably increased our understanding of the complexity of the disease, but still many questions remain unanswered, and the burden of recurrent cardiovascular events remains unacceptable, despite optimal treatment with contemporary intervention and pharmacologic agents.

Our previous findings that prenylcysteine oxidase 1 (PCYOX1) represents a novel lipoprotein-associated protein, and that lipoproteins can themselves generate the reactive oxygen species H₂O₂ through the action of PCYOX1, prompted us to investigate the biological role of this unique enzyme in the development of atherosclerosis.

Methods

Gene silencing approaches with proteomic and biochemical analysis have been introduced to study PCYOX1 biological functions. In vivo localization of PCYOX1 has been performed in human atherosclerotic lesions and aortic arch of ApoE^-/- mice. A double knockout mouse model (PCYOX1^−/−/apoE^−/− mice) was treated with Western-type diet in order to study atherosclerotic lesion progression and the inflammatory status.

Results

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, improves plasma lipid profile, and reduces inflammation.

Conclusions

Collectively, these findings identify the pro-oxidant enzyme PCYOX1 as a novel player in atherogenesis and, therefore, understanding the biology and mechanisms of all functions of this unique enzyme is likely to provide significant therapeutic opportunities in addressing atherosclerosis