Clock genes display rhythmic expression in human hearts.
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.
Leibetseder
Valentin
V
Center of Physiology and Pharmacology, University Vienna, Austria. valentin.leibetseder@meduniwien.ac.at
Humpeler
Susanne
S
Svoboda
Martin
M
Schmid
Diethart
D
Thalhammer
Theresia
T
Zuckermann
Andreas
A
Marktl
Wolfgang
W
Ekmekcioglu
Cem
C
D056930:ARNTL Transcription Factors; D000293:Adolescent; D000328:Adult; D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D009202:Cardiomyopathies / Q000235:genetics / Q000503:physiopathology; D002940:Circadian Rhythm / Q000235:genetics*; D003327:Coronary Disease / Q000235:genetics / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000503:physiopathology; D005260:Female; D006321:Heart / Q000502:physiology* / Q000503:physiopathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D056950:Period Circadian Proteins; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics*; D012016:Reference Values; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C538960:BMAL1 protein, human; C539022:PER1 protein, human; C421902:PER2 protein, human