The progression of atherosclerosis begins with interactions between leukocytes and endothelial cells in a process known as endothelial inflammation. Notably, patients with coronary artery disease have significantly higher serum 7-ketocholesterol levels than those with normal coronary artery disease. ħ-Ketocholesterol has also been detected at high concentrations in oxidized low-density lipoprotein (LDL) within high concentrations in atherosclerotic plaques, which contribute to the development of atherosclerosis. Several studies have also shown that 7-ketocholesterol decreases NO-induced vascular relaxation and induces apoptosis in smooth muscle cells. Additionally, it enhances the expression of vascular endothelial growth factor (VEGF) and inflammatory cytokines.
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Specifically, this oxysterol is a product of cholesterol autoxidation that forms via two known non-enzymatic mechanisms: singlet oxygen, which requires a photosensitizing agent, and free radicals, which require a transition metal catalyst.ħ-Ketocholesterol exhibits both proinflammatory and cytotoxic properties that lead to atherosclerosis. 7-Ketocholesterol is a major dietary oxysterol component. Both dietary oxysterols and cholesterols are absorbed in the intestine by the cholesterol transporter Niemann-Pick C1-like 1 (NPC1L1). High levels of oxysterols, a product of cholesterol oxidation, are found in typical cholesterol-rich foods such as dairy, egg and meat products that have been heated or stored for long periods (Br J Nutr 2002). This does not alter our adherence to PLOS ONE policies on sharing data and materials. The authors have no conflicts of interest directly relevant to the content of this article. The sponsors had no control over the study design, data collection, interpretation, writing, or publication of this work. Research grant for this work was provided by Astellas Pharma Inc (MT and MY), Takeda Pharmaceutical Company Limited (MY), Daiichi Sankyo Company Limited (MY), MSD K.K. and Mitsubishi Tanabe Pharma Corporation provided support in the form of salaries for author MT. The specific roles of these authors are articulated in the ‘author contributions’ section.Ĭompeting interests: MSD K.K. and Mitsubishi Tanabe Pharma Corporation provided support in the form of salaries for author MT, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 16K15439 to MY and MO), the Mishima Kaiun Memorial Foundation ( ) (MT), Astellas Pharma Inc (MT and MY), Takeda Pharmaceutical Company Limited (MY), Daiichi Sankyo Company Limited (MY), MSD K.K. 15K16202 to MT), Grant-in-Aid for Exploratory Research (grant no. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: All relevant data are within the paper.įunding: This work was supported by JSPS KAKENHI Grant-in-Aid for Young Scientists (B) (grant no. Received: ApAccepted: JPublished: July 31, 2018Ĭopyright: © 2018 Tani et al. PLoS ONE 13(7):Įditor: Partha Mukhopadhyay, National Institutes of Health, UNITED STATES These findings suggest that 7-ketocholesterol enhances leukocyte–endothelial interactions by upregulating the expression of adhesion molecules, presumably via the p38 MAPK-dependent pathway.Ĭitation: Tani M, Kamata Y, Deushi M, Osaka M, Yoshida M (2018) 7-Ketocholesterol enhances leukocyte adhesion to endothelial cells via p38MAPK pathway. 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. 7-Ketocholesterol enhanced the expression of E-selectin, ICAM-1, and VCAM-1 proteins. 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). This study aimed to investigate the effects of 7-ketocholesterol on endothelial inflammation, as well as the underlying mechanisms. 7-Ketocholesterol is a major dietary cholesterol oxidation product found in high concentrations in atherosclerotic plaques, which contribute to the development of atherosclerosis.
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