Rapid attenuation of circadian clock gene oscillations in the rat heart following ischemia-reperfusion.
The intracellular circadian clock consists of a series of transcriptional modulators that together allow the cell to perceive the time of day. Circadian clocks have been identified within various components of the cardiovascular system (e.g. cardiomyocytes, vascular smooth muscle cells) and possess the potential to regulate numerous aspects of cardiovascular physiology and pathophysiology. The present study tested the hypothesis that ischemia/reperfusion (I/R; 30 min occlusion of the rat left main coronary artery in vivo) alters the circadian clock within the ischemic, versus non-ischemic, region of the heart. Left ventricular anterior (ischemic) and posterior (non-ischemic) regions were isolated from I/R, sham-operated, and naïve rats over a 24-h period, after which mRNAs encoding for both circadian clock components and known clock-controlled genes were quantified. Circadian clock gene oscillations (i.e. peak-to-trough fold differences) were rapidly attenuated in the I/R, versus the non-ischemic, region. Consistent with decreased circadian clock output, we observe a rapid induction of E4BP4 in the ischemic region of the heart at both the mRNA and protein levels. In contrast with I/R, chronic (1 week) hypobaric chamber-induced hypoxia did not attenuate oscillations in circadian clock genes in either the left or right ventricle of the rat heart. In conclusion, these data show that in a rodent model of myocardial I/R, circadian clocks within the ischemic region become rapidly impaired, through a mechanism that appears to be independent of hypoxia.
Kung
Theodore A
TA
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106, USA.
Egbejimi
Oluwaseun
O
Cui
Jiajia
J
Ha
Ngan P
NP
Durgan
David J
DJ
Essop
M Faadiel
MF
Bray
Molly S
MS
Shaw
Chad A
CA
Hardin
Paul E
PE
Stanley
William C
WC
Young
Martin E
ME
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001683:Biological Clocks / Q000235:genetics*; D056926:CLOCK Proteins; D015687:Cell Hypoxia; D002940:Circadian Rhythm / Q000235:genetics*; D005786:Gene Expression Regulation; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D015534:Trans-Activators; C538945:Clock protein, rat