Tribolo Sandra, Lodi Federica, Connor Carol, Suri Sunita, Wilson Vincent G, Taylor Moira A, Needs Paul W, Kroon Paul A, Hughes David A
Phytochemicals and Health Programme, Institute of Food Research, Norwich Research Park, Norwich NR4 7UA, UK.
Atherosclerosis. 2008 Mar;197(1):50-6. doi: 10.1016/j.atherosclerosis.2007.07.040. Epub 2007 Sep 18.
Adhesion of circulating monocytes to vascular endothelial cells, a critical step in both inflammation and atherosclerosis, is mediated by cross-linkage of adhesion molecules expressed on the surface of both cell types. Dietary flavonoids have been shown to have anti-inflammatory properties, decreasing the expression of cell adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) on endothelial cells. However, flavonoids are efficiently metabolised during absorption and the forms reaching the systemic circulation are glucuronidated, sulphated and methylated. Most previous in vitro studies of the effects of flavonoids have used the parent compounds at concentrations far higher than those physiologically achievable. We investigated the ability of quercetin and its human metabolites, at physiological concentrations (2 micromol/L and 10 micromol/L), to attenuate the inflammation-induced upregulated expression of VCAM-1, ICAM-1 and of the chemokine, monocyte chemoattractant protein-1 (MCP-1), in human umbilical vein endothelial cells (HUVECs), at the protein and transcript levels. Quercetin treatment reduced the inflammation-induced over-expression of VCAM-1 and ICAM-1 (protein and transcript) in HUVECs. Quercetin also inhibited MCP-1 gene expression. However, quercetin 3'-sulfate, quercetin 3-glucuronide and 3'-methylquercetin 3-glucuronide (isorhamnetin 3-glucuronide) generally exhibited either a reduced ability to inhibit the expression of these molecules compared with the parent aglycone or had no effect. However, all three metabolites inhibited VCAM-1 cell surface expression at 2 micromol/L. These results indicate that both quercetin and its metabolites, at physiological concentrations, can inhibit the expression of key molecules involved in monocyte recruitment during the early stages of atherosclerosis.
循环单核细胞与血管内皮细胞的黏附是炎症和动脉粥样硬化中的关键步骤，这一过程由两种细胞表面表达的黏附分子交联介导。膳食类黄酮已被证明具有抗炎特性，可降低内皮细胞上细胞黏附分子的表达，如血管细胞黏附分子-1（VCAM-1）和细胞间黏附分子-1（ICAM-1）。然而，类黄酮在吸收过程中会被有效代谢，进入体循环的形式是葡萄糖醛酸化、硫酸化和甲基化的。以往大多数关于类黄酮作用的体外研究使用的母体化合物浓度远远高于生理可达到的浓度。我们研究了槲皮素及其人体代谢产物在生理浓度（2微摩尔/升和10微摩尔/升）下，在蛋白质和转录水平上减弱炎症诱导的人脐静脉内皮细胞（HUVECs）中VCAM-1、ICAM-1和趋化因子单核细胞趋化蛋白-1（MCP-1）表达上调的能力。槲皮素处理降低了炎症诱导的HUVECs中VCAM-1和ICAM-1（蛋白质和转录本）的过表达。槲皮素还抑制了MCP-1基因的表达。然而，与母体苷元相比，槲皮素3'-硫酸盐、槲皮素3-葡萄糖醛酸苷和3'-甲基槲皮素3-葡萄糖醛酸苷（异鼠李素3-葡萄糖醛酸苷）通常表现出抑制这些分子表达的能力降低或没有作用。然而，所有三种代谢产物在2微摩尔/升时均抑制了VCAM-1的细胞表面表达。这些结果表明，在生理浓度下，槲皮素及其代谢产物均可抑制动脉粥样硬化早期单核细胞募集过程中关键分子的表达。
