|Kung, Theodore - CASE WSTRN, CLEVELAND, OH|
|Egbejimi, Oluwaseun - BAYLOR COLLEGE MED|
|Cui, Jiajia - CASE WSTRN, CELVELAND, OH|
|Ha, Ngan - BAYLOR COLLEGE MED|
|Durgan, David - BAYLOR COLLEGE MED|
|Essop, M - U CAPE TOWN, S AFRICA|
|Shaw, Chad - BAYLOR COLLEGE MED|
|Hardin, Paul - TAMU, COLLEGE STATION, TX|
|Stanley, William - CASE WSTRN, CLEVELAND, OH|
Submitted to: Journal of Molecular and Cellular Cardiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: August 27, 2007
Publication Date: December 1, 2007
Citation: Kung, T.A., Egbejimi, O., Cui, J., Ha, N.P., Durgan, D.J., Essop, M.F., Bray, M.S., Shaw, C.A., Hardin, P.E., Stanley, W.C., Young, M.E. 2007. Rapid attenuation of circadian clock gene oscillations in the rat heart following ischemia-reperfusion. Journal of Molecular and Cellular Cardiology. 43(6):744-753. Interpretive Summary: Nearly every cell in the body contains a set of molecules that regulate daily rhythms in many cellular functions – together these molecules comprise the circadian clock. In heart cells, these circadian clocks appear to regulate some aspects of heart function. The present study tested the idea that loss of oxygen and nutrients to the heart cells resulting from decreased blood flow or blockage of the heart vessels, followed by increased blood flow to the heart, can alter the circadian clock within heart cells. In an experiment that simulated decreased blood flow in the heart followed by increased blood flow, we found that the circadian clock in heart cells was impaired by such events and that this impairment did not appear to be related only to loss of oxygen.
Technical 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 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.