Molecular mechanisms of morning onset of myocardial infarction.
We recently isolated a novel bHLH/PAS protein, CLIF (cycle like factor), by yeast two-hybrid screening of human umbilical endothelial cell cDNA library. CLIF is preferentially expressed in endothelial and neuronal cells. Because CLIF is expressed in vascular endothelial cells and forms a heterodimer with CLOCK, the key transcription factor controlling the circadian rhythm, we hypothesized that CLIF regulates the circadian oscillation of PAI-1 gene expression in endothelial cells. Northern blot analysis of mouse organs showed circadian oscillations of PAI-I mRNA levels. In addition, the clock-related genes also showed circadian oscillation in peripheral tissues. In endothelial cells, the heterodimer of CLIF and CLOCK upregulated the PAI-1 gene expression through E-box sites. Furthermore, Period and Cryptochrome, which are negative regulators in the feedback loop of the biological clock, inhibited PAI-1 promoter activation by the CLOCK:CLIF heterodimer. These results suggest that the peripheral tissues have their own biological clock and CLIF regulates the circadian oscillation of PAI-1 gene expression in endothelial cells. This study suggests a novel molecular mechanism of the morning onset of myocardial infarction. Here we review our recent work and literature.
Maemura
K
K
Department of Cardiovascular Medicine, Tokyo University Graduate School of Medicine, Japan. kmae-tky@umin.ac.jp
Layne
M D
MD
Watanabe
M
M
Perrell
M A
MA
Nagai
R
R
Lee
M E
ME
D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002940:Circadian Rhythm / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D008954:Models, Biological; D009203:Myocardial Infarction / Q000235:genetics / Q000503:physiopathology*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D014176:Protein Biosynthesis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D017395:Plasminogen Activator Inhibitor 1; D014157:Transcription Factors; C486615:BMAL2 protein, human