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Regulation of the PAI-1 promoter by circadian clock components: differential activation by BMAL1 and BMAL2

John A Schoenhard1, Layton H Smith, Corrie A Painter

  • 1Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, 2220 Pierce Avenue, 383 PRB, Nashville, TN 37232, USA.

Journal of Molecular and Cellular Cardiology
|May 10, 2003
PubMed

Insights

Circadian clock proteins CLOCK:BMAL1 and CLOCK:BMAL2 regulate plasminogen activator inhibitor-1 (PAI-1) gene transcription. This regulation influences the timing of heart attacks and thrombolytic therapy effectiveness.

Area of Science:

  • Molecular Biology
  • Chronobiology
  • Cardiovascular Research

Background:

  • Circadian variation in plasminogen activator inhibitor-1 (PAI-1) is linked to morning myocardial infarction risk and reduced thrombolytic therapy efficacy.
  • Understanding the molecular mechanisms regulating PAI-1 circadian rhythm is crucial for cardiovascular health.

Purpose of the Study:

  • To investigate how core circadian clock components regulate the human PAI-1 promoter in endothelial cells.
  • To determine the role of CLOCK:BMAL1 and CLOCK:BMAL2 heterodimers in PAI-1 gene transcription.

Main Methods:

  • Transfection of endothelial cells with human PAI-1 promoter constructs.
  • Analysis of promoter activity regulated by CLOCK:BMAL1 and CLOCK:BMAL2 heterodimers.
  • Investigation of the influence of the PAI-1 4G/5G polymorphism on promoter activity.

Main Results:

  • Both CLOCK:BMAL1 and CLOCK:BMAL2 heterodimers activate the PAI-1 promoter via proximal and distal E-box enhancers.
  • The 4G/5G polymorphism at the distal E-box does not affect transactivation by CLOCK:BMAL1 or CLOCK:BMAL2.
  • CLOCK:BMAL1 and CLOCK:BMAL2 contribute additively to PAI-1 gene transcription, with differential activation but equivalent inhibition susceptibility.

Conclusions:

  • Core circadian clock components CLOCK:BMAL1 and CLOCK:BMAL2 are key regulators of human PAI-1 transcription.
  • These molecular interactions provide a basis for circadian variation in PAI-1 and its impact on atherothrombotic events.
  • Understanding these mechanisms may inform strategies for managing cardiovascular events and optimizing thrombolytic therapy.

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