Neutrophil proteinase 3-An LDL- and HDL-proteolyzing enzyme with a potential to contribute to cholesterol accumulation in human atherosclerotic lesions
Biochimica et biophysica acta. Molecular and cell biology of lipids(2022)
Abstract
Neutrophil proteinase 3 (PR3) is a multifunctional neutral serine protease involved in the regulation of pro-inflammatory processes, but its potential causal roles in the lipid-driven responses in atherosclerosis have remained unexplored. This study aimed to investigate the presence of PR3 in human atherosclerotic lesions and the ability of this protease to modify the structure and functions of LDL and HDL particles in vitro. Coronary artery segments were collected from autopsied subjects and immunostained for PR3. Atherosclerotic lesions but not normal intima contained PR3. Incubation of LDL particles with the PR3 led to extensive degradation of their apoB-100 component and strongly increased their binding strength to isolated human aortic proteoglycans in vitro. Moreover, cultured human monocyte-derived macrophages avidly ingested the PR3-modified LDL particles and were converted into foam cells. Incubation of HDL particles with PR3 led to proteolysis of their major apolipoproteins (apoA-I, apoA-II, and apoE) and impaired their ability to promote cholesterol efflux from the macrophage foam cells. We conclude that PR3 is present in human atherosclerotic lesions and that this neutral serine protease has proatherogenic properties. Thus, by proteolytically modifying LDL and HDL particles, PR3 may promote cholesterol accumulation both extra-and intracellularly in atherosclerotic lesions, and so contribute to the lipid-driven component of atherogenesis.
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Key words
LDL,HDL,Macrophages,Neutrophils,Neutral proteases,Proteoglycans,Proteinase-3
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