CLIF, a novel cycle-like factor, regulates the circadian oscillation of plasminogen activator inhibitor-1 gene expression

The onset of myocardial infarction occurs frequently in the early morning, and it may partly result from circadian variation of fibrinolytic activity. Plasminogen activator inhibitor-1 activity shows a circadian oscillation a nd may account for the morning onset of myocardial infarction, However, the molecular mechanisms regulating this circadian oscillation remain unknown. Recent evidence indicates that basic helix-loop-helix (bHLH)/PAS domain tr anscription factors play a crucial role in controlling the biological clock that controls circadian rhythm. We isolated a novel bHLH/PAS protein, cycl e-like factor (CLIF) rom human umbilical vein endothelial cells. CLIF share s high homology with Drosophila CYCLE, one of the essential transcriptional regulators of circadian rhythm. CLIF is expressed in endothelial cells and neurons in the brain, including the suprachiasmatic nucleus, the center of the circadian clock, In endothelial cells, CLIF forms a heterodimer with C LOCK and up-regulates the PAI-1 gene through E-box sites. Furthermore, Peri od2 and Cryptochrome1, whose expression show a circadian oscillation in per ipheral tissues, inhibit the PAI-1 promoter activation by the CLOCK:CLIF he terodimer. These results suggest that CLIF regulates the circadian oscillat ion of PAI-1 gene expression in endothelial cells. In addition, the results potentially provide a molecular basis for the morning onset of myocardial infarction,