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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

The Journal of Biological Chemistry
|October 6, 2000
PubMed

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.

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