7-keto Cholesterol is a major oxysterol associated with vascular disease. It is widely present in atherosclerotic plaques and has a stronger atherogenic effect than cholesterol[1]. 7-keto Cholesterol can inhibit the rate-limiting enzymes involved in the synthesis of bile acids and cholesterol, such as cholesterol 7α-hydroxylase and HMG-CoA reductase[2]. 7-keto Cholesterol has pro-inflammatory effects[3].
In vitro, 7-keto Cholesterol (50μM) treatment of human umbilical vein endothelial cells (HUVECs) for 18h upregulated the expression of adhesion molecules (especially E-selectin), enhanced the expression of IL-8 mRNA, and enhanced the activity of NF-κB[4]. 7-keto Cholesterol (2.5-40μg/mL) treatment of human microvascular endothelial cells (HMVECs) dose-dependently inhibited cell viability and activated caspase-3/7, -8 and -12[5]. Treatment of vascular smooth muscle cells (VSMCs) with 7-keto Cholesterol (5μg/mL) for 24h significantly increased the expression of interleukin-6 (IL-6)[6].
In vivo, 7-keto Cholesterol (0.1%) added to the diet of mice treated with ischemia-reperfusion (IR) injury for 3 weeks increased the level of 7-keto Cholesterol in mouse plasma and increased the size of myocardial infarction after IR[7].
References:
[1] Brahmi F, Vejux A, Sghaier R, et al. Prevention of 7-ketocholesterol-induced side effects by natural compounds[J]. Critical reviews in food science and nutrition, 2019, 59(19): 3179-3198.
[2] Morin R J, Peng S K. Cholesterol oxides in plasma and tissues[J]. Biological effects of cholesterol oxides, 1992: 89-101.
[3] Alba G, Reyes-Quiróz M E, Sáenz J, et al. 7-Keto-cholesterol and 25-hydroxy-1 cholesterol rapidly enhance ROS production in human neutrophils[J]. European journal of nutrition, 2016, 55: 2485-2492.
[4] Tani M, Kamata Y, Deushi M, et al. 7-Ketocholesterol enhances leukocyte adhesion to endothelial cells via p38MAPK pathway[J]. PLoS One, 2018, 13(7): e0200499.
[5] Luthra S, Dong J, Gramajo A L, et al. 7-Ketocholesterol activates caspases-3/7,-8, and-12 in human microvascular endothelial cells in vitro[J]. Microvascular research, 2008, 75(3): 343-350.
[6] Sung S C, Kim K, Lee K A, et al. 7-Ketocholesterol upregulates interleukin-6 via mechanisms that are distinct from those of tumor necrosis factor-α, in vascular smooth muscle cells[J]. Journal of vascular research, 2008, 46(1): 36-44.
[7] Uchikawa T, Matoba T, Kawahara T, et al. Dietary 7-ketocholesterol exacerbates myocardial ischemia–reperfusion injury in mice through monocyte/macrophage-mediated inflammation[J]. Scientific reports, 2022, 12(1): 14902.
7-keto Cholesterol是一种与血管疾病相关的主要氧甾醇，广泛存在于动脉粥样硬化斑块中，具有比胆固醇更强的致动脉粥样硬化作用[1]。7-keto Cholesterol能够抑制参与胆汁酸和胆固醇合成的限速酶，如胆固醇7α-羟化酶和HMG-CoA还原酶[2]。7-keto Cholesterol具有促炎作用[3]。
在体外，7-keto Cholesterol（50μM）处理人脐静脉内皮细胞（HUVECs）18h，上调了粘附分子（特别是E-选择素）的表达，增强了IL-8 mRNA的表达，增强了NF-κB的活性[4]。7-keto Cholesterol（2.5-40μg/mL）处理人微血管内皮细胞（HMVEC），剂量依赖性地抑制了细胞活力，激活了caspase-3/7、-8和-12[5]。7-keto Cholesterol（5μg/mL）处理血管平滑肌细胞（VSMC）24h，显著增加了白细胞介素-6（IL-6）的表达[6]。
在体内，7-keto Cholesterol（0.1%）添加到饮食中治疗缺血再灌注（IR）损伤小鼠3周，升高了小鼠血浆中7-keto Cholesterol水平，增加了IR后的心肌梗塞面积[7]。