The orphan nuclear receptor Rev-erbα regulates circadian expression of plasminogen activator inhibitor type 1

被引:104
作者
Wang, Jing
Yin, Lei
Lazar, Mitchell A.
机构
[1] Univ Penn, Sch Med, Div Endocrinol Diabet & Metab, Dept Med, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA
关键词
D O I
10.1074/jbc.M607873200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 alpha, a core component of the circadian loop, represses human PAI-1 gene expression through two Rev-erb alpha binding sites in the PAI-1 promoter. Mutations of these sites, as well as RNA interference targeting endogenous Rev-erb alpha and its corepressors, led to increased expression of the PAI-1 gene. Furthermore, glycogen synthase kinase 3 beta (GSK3 beta) contributes to pai-1 repression by phosphorylating and stabilizing Rev-erb alpha 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 alpha that mimics GSK3 beta phosphorylation dramatically dampened PAI-1 circadian oscillations. Thus, our results suggest that Rev-erb alpha is a major determinant of the circadian PAI-1 expression and a potential modulator of the morning susceptibility to myocardial infarction.
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页码:33842 / 33848
页数:7
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