Related Experiment Videos
CLIF, a novel cycle-like factor, regulates the circadian oscillation of plasminogen activator inhibitor-1 gene
K Maemura1, S M de la Monte, M T Chin
1Cardiovascular and the Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. kmae-tky@umin.ac.jp
Insights
A novel protein, cycle-like factor (CLIF), regulates circadian rhythm in endothelial cells, controlling plasminogen activator inhibitor-1 (PAI-1) gene expression. This discovery may explain the morning onset of myocardial infarction.
Area of Science:
- Molecular Biology
- Chronobiology
- Cardiovascular Research
Background:
- Myocardial infarction frequently occurs in the early morning, potentially linked to circadian variations in fibrinolytic activity.
- Plasminogen activator inhibitor-1 (PAI-1) activity exhibits circadian oscillations, which may contribute to the morning peak of myocardial infarction incidence.
- The molecular mechanisms underlying PAI-1 circadian oscillation are not fully understood.
Purpose of the Study:
- To identify novel molecular regulators of circadian rhythm in endothelial cells.
- To elucidate the role of these regulators in controlling PAI-1 gene expression.
- To explore the potential link between these mechanisms and the morning onset of myocardial infarction.
Main Methods:
- Isolation and characterization of a novel bHLH/PAS protein, cycle-like factor (CLIF), from human umbilical vein endothelial cells.
- Investigation of CLIF expression patterns in endothelial cells and brain regions.
- Analysis of CLIF's interaction with CLOCK and its effect on PAI-1 gene regulation, including the role of Period2 and Cryptochrome1.
Main Results:
- CLIF, a novel bHLH/PAS protein homologous to Drosophila CYCLE, was identified in endothelial cells.
- CLIF forms a heterodimer with CLOCK in endothelial cells, up-regulating PAI-1 gene expression via E-box elements.
- Period2 and Cryptochrome1 were found to inhibit PAI-1 promoter activation by the CLOCK:CLIF complex.
Conclusions:
- CLIF plays a significant role in regulating the circadian oscillation of PAI-1 gene expression within endothelial cells.
- These findings provide a potential molecular basis for understanding the morning predilection of myocardial infarction.
- The study highlights the importance of circadian clock components in cardiovascular health and disease.
Abstract:
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 and 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 transcription factors play a crucial role in controlling the biological clock that controls circadian rhythm. We isolated a novel bHLH/PAS protein, cycle-like factor (CLIF) from human umbilical vein endothelial cells. CLIF shares 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 CLOCK and up-regulates the PAI-1 gene through E-box sites. Furthermore, Period2 and Cryptochrome1, whose expression show a circadian oscillation in peripheral tissues, inhibit the PAI-1 promoter activation by the CLOCK:CLIF heterodimer. These results suggest that CLIF regulates the circadian oscillation of PAI-1 gene expression in endothelial cells. In addition, the results potentially provide a molecular basis for the morning onset of myocardial infarction.