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J. Biol. Chem., Vol. 283, Issue 14, 9424-9434, April 4, 2008

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Macrophage as a Target of Quercetin Glucuronides in Human Atherosclerotic Arteries

IMPLICATION IN THE ANTI-ATHEROSCLEROTIC MECHANISM OF DIETARY FLAVONOIDS^*

Yoshichika Kawai¹, Tomomi Nishikawa, Yuko Shiba, Satomi Saito, Kaeko Murota, Noriyuki Shibata, Makio Kobayashi, Masaya Kanayama^¶, Koji Uchida^¶, and Junji Terao

From the Department of Food Science, Graduate School of Nutrition and Biosciences, the University of Tokushima, Tokushima 770-8503, the Department of Pathology, Tokyo Women's Medical University, Tokyo 162-8666, and ^¶Laboratory of Food and Biodynamics, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan

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.

Received for publication, August 8, 2007 , and in revised form, January 14, 2008.

^* This work was supported in part by a grant-in-aid for young scientists (to Y. K.) from the Ministry of Education, Culture, Sports, Science, and Technology, by the Ministry of Agriculture, Forestry and Fishery Food Project, Japan, by the Center of Excellence Program in the 21st Century in Japan, and by the 2007 Danon Institute of Japan Research Grant. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed. Tel.: 81-88-633-9592; Fax: 81-88-633-7089; E-mail: y-kawai{at}nutr.med.tokushima-u.ac.jp.

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