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J. Biol. Chem., Vol. 281, Issue 45, 33842-33848, November 10, 2006
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The Orphan Nuclear Receptor Rev-erb
Regulates Circadian Expression of Plasminogen Activator Inhibitor Type 1*
From the Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and the Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
Plasminogen activator inhibitor type 1 (PAI-1) is a major physiologic regulator of the fibrinolytic system and has recently gained recognition as a modulator of inflammation and atherosclerosis. PAI-1 exhibits circadian rhythmicity in its expression, peaking in the early morning, which is associated with increased risk for cardiovascular events. However, the mechanisms that determine PAI-1 circadian rhythmicity remain poorly understood. We discovered that the orphan nuclear receptor Reverb
, a core component of the circadian loop, represses human PAI-1 gene expression through two Rev-erb binding sites in the PAI-1 promoter. Mutations of these sites, as well as RNA interference targeting endogenous Rev-erb and its corepressors, led to increased expression of the PAI-1 gene. Furthermore, glycogen synthase kinase 3
(GSK3) contributes to pai-1 repression by phosphorylating and stabilizing Rev-erb protein, which can be blocked by lithium. Interestingly, serum shock generated circadian oscillations in PAI-1 mRNA in NIH3T3 cells, suggesting that PAI-1 is a direct output gene of the circadian loop. Ectopic expression of a stabilized form of Rev-erb that mimics GSK3 phosphorylation dramatically dampened PAI-1 circadian oscillations. Thus, our results suggest that Rev-erb is a major determinant of the circadian PAI-1 expression and a potential modulator of the morning susceptibility to myocardial infarction.
Received for publication, August 17, 2006 , and in revised form, September 11, 2006.
* This work was supported in part by National Institutes of Health Grant DK45586 (to M. A. L.). 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.
1 Supported in part by a Medical Scientist Training Program grant to the University of Pennsylvania.
2 To whom correspondence should be addressed: University of Pennsylvania School of Medicine, 611 Clinical Research Bldg., 415 Curie Blvd., Philadelphia, PA 19104-6149. Tel.: 215-898-0198; Fax: 215-898-5408; E-mail: lazar{at}mail.med.upenn.edu.
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