Abstract
7-Ketocholesterol is a major dietary cholesterol oxidation product found in high concentrations in atherosclerotic plaques, which contribute to the development of atherosclerosis. This study aimed to investigate the effects of 7-ketocholesterol on endothelial inflammation, as well as the underlying mechanisms. Pretreatment of human umbilical vein endothelial cells (HUVEC) with 7-ketocholesterol significantly enhanced the total interactions between human monocytic cells (THP-1 cell line) and TNFα-activated HUVECs under physiological flow conditions, compared to pretreatment with cholesterol (TNFα+50 μM cholesterol: 13.1 ± 0.54 cells/CPF, TNFα+50 μM 7-ketocholesterol: 18.9 ± 0.35 cells/CPF, p < 0.01). 7-Ketocholesterol enhanced the expression of E-selectin, ICAM-1, and VCAM-1 proteins. It also activated p38 mitogen-activated protein kinase (MAPK), and treatment with a p38 MAPK inhibitor inhibited both E-selectin expression via ATF-2 activation and 7-ketocholesterol-induced THP-1 adhesion to HUVECs. These findings suggest that 7-ketocholesterol enhances leukocyte–endothelial interactions by upregulating the expression of adhesion molecules, presumably via the p38 MAPK-dependent pathway.
Highlights
High levels of oxysterols, a product of cholesterol oxidation, are found in typical cholesterolrich foods such as dairy, egg and meat products that have been heated or stored for long periods (Br J Nutr 2002)
Leukocyte–endothelial interactions have been recognized as crucial factors in the development of atherosclerosis and subsequent cardiovascular disease. 7-Ketocholesterol is a major dietary oxysterol and component of the non-enzymatic cholesterol oxidation pathway, along with singlet oxygen and free radical oxidation [16,17]
The adhesion of monocytes to endothelial cells is responsible for monocyte infiltration and subsequent differentiation into macrophages, which contribute to the formation of atherosclerotic lesions
Summary
A product of cholesterol oxidation, are found in typical cholesterolrich foods such as dairy, egg and meat products that have been heated or stored for long periods (Br J Nutr 2002). Both dietary oxysterols and cholesterols are absorbed in the intestine by the cholesterol transporter Niemann-Pick C1-like 1 (NPC1L1). 7-Ketocholesterol exhibits both proinflammatory and cytotoxic properties that lead to atherosclerosis. It enhances the expression of vascular endothelial growth factor (VEGF) [1] and inflammatory cytokines [2]. Several studies have shown that 7-ketocholesterol decreases NO-induced vascular relaxation [3,4,5] and induces apoptosis in smooth muscle cells [6].
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