期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 129, 期 -, 页码 354-363出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2018.09.046
关键词
Atherosclerosis; Inflammation, Plaque instability; 27-Hydroxycholesterol; 4-Hydroxynonenal
资金
- University of Turin (Italy) [LEOG_RILO_17_01]
Atherosclerosis is currently understood to be mainly the consequence of a complicated inflammatory process at the different stages of plaque development. Among the several inflammatory molecules involved, up-regulation of the functional cyclooxygenase 2/membrane-bound prostaglandin E synthase 1 (COX-2/mPGES-1) axis plays a key role in plaque development. Excessive production of oxidized lipids, following low-density lipoprotein (LDL) oxidation, is a characteristic feature of atherosclerosis. Among the oxidized lipids of LDLs, the oxysterol 27-hydroxycholesterol (27-OH) and the aldehyde 4-hydroxynonenal (HNE) substantially accumulate in the atherosclerotic plaque, contributing to its progression and instability through a variety of processes. This study shows that 27-OH and HNE promote up-regulation of both the inducible enzymes COX-2 and mPGES-1, leading to increased production of prostaglandin (PG) E-2 and inducible nitric oxide synthase, and the subsequent release of nitric oxide in human promonocytic U937 cells. The study also examined the potential involvement of the functionally coupled COX-2/mPGES-1 in enhancing the production of certain pro-inflammatory cytokines and of matrix metalloproteinase 9 by U937 cells. This enhancement is presumably due to the induction of PGE(2) synthesis, as a result of the up-regulation of the COX-2/mPGES-1, stimulated by the two oxidized lipids, 27-OH and HNE. Induction of PGE(2) synthesis might thus be a mechanism of plaque instability and eventual rupture, contributing to matrix metalloproteinase production by activated macrophages.
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