Macrophage as a target of quercetin glucuronides in human atherosclerotic arteries - Implication in the anti-atherosclerotic mechanism of dietary flavonoids
Macrophage as a target of quercetin glucuronides in human atherosclerotic arteries - Implication in the anti-atherosclerotic mechanism of dietary flavonoids
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DOI：
10.1074/jbc.m706571200
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发表时间：
2008-04-04
影响因子：
4.8
通讯作者：
Terao, Junji
中科院分区：
文献类型：
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作者：
Kawai, Yoshichika;Nishikawa, Tomomi;Terao, Junji
流行病学研究表明，食用富含类黄酮的饮食可以降低患心血管疾病的风险。然而，黄酮类化合物在体内保护机制的靶位点尚不清楚。槲皮素代表广泛分布于人类饮食中的抗氧化/抗炎类黄酮。在这项研究中，我们提出了一种新的单克隆抗体14 A2靶向槲皮素-3-葡萄糖醛酸苷（Q3 GA），一个主要的抗氧化槲皮素代谢产物在人血浆中，并发现激活的巨噬细胞可能是一个潜在的目标，膳食黄酮在主动脉。单克隆抗体14 A2的免疫组化研究表明，阳性染色特异性地积累在人类动脉粥样硬化病变，但不是在正常的主动脉，和强烈的染色主要与巨噬细胞源性泡沫细胞。鼠巨噬细胞系的体外实验表明，在活化的巨噬细胞中，Q3 GA被显著摄取并解偶联成活性更高的糖苷配基，其中一部分进一步转化为甲基化形式。此外，类清道夫受体和CD 36的mRNA表达，这对泡沫细胞的形成起着重要作用，被抑制的Q3 GA的处理。这些结果表明，具有活化的巨噬细胞的损伤/发炎的动脉是膳食槲皮素的代谢物的潜在靶点。我们的数据为膳食黄酮的生物利用度和预防心血管疾病的机制提供了新的见解。
Epidemiological studies suggest that the consumption of flavonoid-rich diets decreases the risk of cardiovascular diseases. However, the target sites of flavonoids underlying the protective mechanism in vivo are not known. Quercetin represents antioxidative/anti-inflammatory flavonoids widely distributed in the human diet. In this study, we raised a novel monoclonal antibody 14A2 targeting the quercetin-3-glucuronide (Q3GA), a major antioxidative quercetin metabolite in human plasma, and found that the activated macrophage might be a potential target of dietary flavonoids in the aorta. Immunohistochemical studies with monoclonal antibody 14A2 demonstrated that the positive staining specifically accumulates in human atherosclerotic lesions, but not in the normal aorta, and that the intense staining was primarily associated with the macrophage-derived foam cells. In vitro experiments with murine macrophage cell lines showed that the Q3GA was significantly taken up and deconjugated into the much more active aglycone, a part of which was further converted to the methylated form, in the activated macrophages. In addition, the mRNA expression of the class A scavenger receptor and CD36, which play an important role for the formation of foam cells, was suppressed by the treatment of Q3GA. These results suggest that injured/inflamed arteries with activated macrophages are the potential targets of the metabolites of dietary quercetin. Our data provide a new insight into the bioavailability of dietary flavonoids and the mechanism for the prevention of cardiovascular diseases.