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J. Biol. Chem., Vol. 282, Issue 45, 32561-32567, November 9, 2007

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Thrombomodulin Is a Clock-controlled Gene in Vascular Endothelial Cells^*

Norihiko Takeda¹, Koji Maemura¹², Shuichi Horie, Katsutaka Oishi^¶, Yasushi Imai, Tomohiro Harada, Tetsuya Saito, Taro Shiga, Eisuke Amiya, Ichiro Manabe, Norio Ishida^¶, and Ryozo Nagai

From the Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan, Kagawa Nutrition University, Saitama 350-0288, Japan, and ^¶National Institute of Advanced Industrial Science and Technology, Tsukuba 305-8568, Japan

Cardiovascular diseases are closely related to circadian rhythm, which is under the control of an internal biological clock mechanism. Although a biological clock exists not only in the hypothalamus but also in each peripheral tissue, the biological relevance of the peripheral clock remains to be elucidated. In this study we searched for clock-controlled genes in vascular endothelial cells using microarray technology. The expression of a total of 229 genes was up-regulated by CLOCK/BMAL2. Among the genes that we identified, we examined the thrombomodulin (TM) gene further, because TM is an integral membrane glycoprotein that is expressed primarily in vascular endothelial cells and plays a major role in the regulation of intravascular coagulation. TM mRNA and protein expression showed a clear circadian oscillation in the mouse lung and heart. Reporter analyses, gel shift assays, and chromatin immunoprecipitation analyses using the TM promoter revealed that a heterodimer of CLOCK and BMAL2 binds directly to the E-box of the TM promoter, resulting in TM promoter transactivation. Indeed, the oscillation of TM gene expression was abolished in clock mutant mice, suggesting that TM expression is regulated by the clock gene in vivo. Finally, the phase of circadian oscillation of TM mRNA expression was altered by temporal feeding restriction, suggesting TM gene expression is regulated by the peripheral clock system. In conclusion, these data suggest that the peripheral clock in vascular endothelial cells regulates TM gene expression and that the oscillation of TM expression may contribute to the circadian variation of cardiovascular events.

Received for publication, July 11, 2007 , and in revised form, September 10, 2007.

^* This study was supported by Grants-in-aid for Scientific Research from the Ministry of Education Science and Culture, Japan, 14370220 and 19590853 (to K. M.) and 17590071 (to S. H.), a Japan Heart Foundation/Pfizer grant for Research on Hypertension and Metabolism (to K. M.), the Takeda Science Foundation (to K. M.), Sankyo Foundation of Life Science (to K. M.), Suzuken Memorial Foundation (to K. M.), Kato Memorial Bioscience Foundation (to N. T.), Japan Foundation of Applied Enzymology (to N. T.), and the Cell Science Research Foundation (to N. T.). 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 and table S1.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 81-3-3818-6672; Fax: 81-3-3815–2087; E-mail: kmae-tky{at}umin.ac.jp.

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