Rapid attenuation of circadian clock gene oscillations in the rat heart following ischemia–reperfusion

Abstract

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 minute 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 hour 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.

Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism, and gene expression

“…As such, both intracellular and extracellular factors should be considered as important mediators of circadian rhythms in cardiovascular function. We speculate that impairment of this molecular mechanism may contribute toward myocardial contractile dysfunction associated with pressure overload, diabetes mellitus, myocardial infarction, and/or shift work (conditions in which the circadian clock within the heart is known to be altered) (9,18,43,45,46). Future studies should focus on addressing this important hypothesis.…”

Is There a Better Time of Day to Have a Heart Attack?

“…Obesity, diabetes mellitus, hypertension, simulated shift work, aging, and ischemia/reperfusion have all been shown to influence this molecular mechanism. 12,[22][23][24][25][26][27] Coupled with the findings by Durgan et al, 21 the possibility arises that alterations in the clock mechanism during disease states contribute to greater tissue damage and contractile dysfunction following myocardial infarction. It remains to be seen if the human myocardium displays a similar response to the circadian clock.…”

Circadian rhythm and cardiovascular disorders

“…This attenuation was not observed with hypoxia induced by a hypobaric chamber, suggesting that the clock machinery is involved in the response to ischemia/reperfusion, independent of hypoxia. 99 Durgan et al showed that wild-type mouse hearts subjected to ischemia/reperfusion at the sleep-to-wake transition (ZT12) had a 3.5-fold increase in infarct size compared with hearts subjected to ischemia/ reperfusion at the wake-to-sleep transition (ZT0) and this variation was abolished in CCM mice. This study provides the first evidence that there is a time-of-day-dependent susceptibility to ischemia/reperfusion that is intrinsic to cardiomyocytes.…”