Clock Genes Display Rhythmic Expression in Human Hearts

Abstract

Thus far, clock genes in the heart have been described only in rodents, and alterations of these genes have been associated with various myocardial malfunctions. In this study, we analyzed the expression of clock genes in human hearts. Left papillary muscles of 16 patients with coronary heart disease, 39 subjects with cardiomyopathy, and 9 healthy donors (52 males and 12 females, mean age 55.7+/-11.2; 16-70 yrs) were obtained during orthotopic heart transplantation. We assessed the mRNA levels of PER1, PER2, BMAL1, and CRY1 by real time PCR and analyzed their rhythmic expression by sliding means and Cosinor functions. Furthermore, we sought for differences between the three groups (by ANOVAs) for both the total 24 h period and separate time bins. All four clock genes were expressed in human hearts. The acrophases (circadian rhythm peak time) of the PER mRNAs occurred in the morning (PER1: 07:44 h [peak level 187% higher than trough, p = .008]; PER2: 09:42 h [peak 254% higher than trough, p < .0001], and BMAL1 mRNA in the evening at 21:44 h [peak 438% higher than trough; p < .0001]. No differences were found in the rhythmic patterns between the three groups. No circadian rhythm was detected in CRY1 mRNA in any group. PER1, PER2, and BMAL1 mRNAs revealed clear circadian rhythms in the human heart, with their staging being in antiphase to those in rodents. The circadian amplitudes of the mRNA clock gene levels in heart tissue are more distinct than in any other human tissue so far investigated. The acrophase of the myocardial PER mRNAs and the trough of the myocardial BMAL1 coincide to the time of day of most frequent myocardial incidents.

Of Mice and Men

“…By periodic sinusoidal regression analysis, they observed that peak infarct size was 82% greater than trough and occurred at 1:00 am onset of ischemia, a time at which the cardiomyocyte clock gene Per 2 is at its nadir in human biopsy samples. 12 These findings were supported by a similar circadian distribution of left ventricular function, with peak ejection fraction coinciding with the trough of peak creatine kinase release. A similar time of peak infarction (from midnight till 6:00 am) to that of Reiter et al 11 was observed by Fournier et al 13 in a cohort (n=355) of 588 consecutive patients with STEMI from Switzerland.…”

Circadian Patterns of ST Elevation Myocardial Infarction in the New Millennium

“…25 We noted an increase in aspirin use from 10.8% in the 1992 study by Tofler recent studies have demonstrated that clock genes in human cardiac tissue display significant time-dependent transcriptional variation with peak expression of some clock genes and trough expression of others coinciding with myocardial incidents. 43 Morning hours may also represent nadir levels of some cardioprotective medications. Together, these hemostatic changes, changes in gene expression, and external triggers may create a shearing stress and cause rupture of vulnerable coronary atherosclerotic plaques in the morning, when an elevated prothrombotic state already exists.…”

On Circadian Variation of Myocardial Reperfusion Injury

“…Most studies of these clocks have been carried out in the fungus Neurospora, in Drosophila and in a variety of rodents, but they have also been found in human cardiac tissue. 4 These peripheral circadian clocks are controlled by so-called "CLOCK" genes that have been found to control approximately 10% of all genes expressed in the mouse heart, which exhibit circadian rhythmicity. 5 This results in cyclic variations in mRNA and protein synthesis and thereby influence cardiac contractile function as well as oxidative and nonoxidative metabolism of carbohydrates and lipids.…”