Clock genes in the heart: characterization and attenuation with hypertrophy.
We investigated whether the heart, like other mammalian organs, possesses internal clocks, and, if so, whether pressure overload-induced hypertrophy alters the clock mechanism. Clock genes are intrinsically maintained, as shown by rhythmic changes even in single cells. Clocks are believed to confer a selective advantage by priming the cell for the expected environmental stimulus. In this way, clocks allow anticipation, thereby synchronizing responsiveness of the cell with the timing of the stimulus. We have found that in rat heart all mammalian homologues of known Drosophila clock genes (bmal1, clock, cry1, cry2, per1, per2, per3, dbp, hlf, and tef) show circadian patterns of expression and that the induction of clock output genes (the PAR [rich in proline and acidic amino acid residues] transcription factors dbp, hlf, and tef) is attenuated in the pressure-overloaded hypertrophied heart. The results expose a new dynamic regulatory system in the heart, which is partially lost with hypertrophy. Although the target genes of these PAR transcription factors are not known in the heart, the results provide evidence for a diminished ability of the hypertrophied heart to anticipate and subsequently adapt to physiological alterations during the day.
Young
M E
ME
Department of Internal Medicine, Division of Cardiology, University of Texas-Houston Medical School, Houston, TX 77030, USA.
Razeghi
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P
Taegtmeyer
H
H
D056930:ARNTL Transcription Factors; D000818:Animals; D001011:Aorta / Q000473:pathology; D051792:Basic Helix-Loop-Helix Proteins; D050976:Basic-Leucine Zipper Transcription Factors; D001683:Biological Clocks / Q000235:genetics*; D015415:Biomarkers / Q000032:analysis; D056926:CLOCK Proteins; D006332:Cardiomegaly / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D002940:Circadian Rhythm; D003251:Constriction, Pathologic / Q000150:complications / Q000473:pathology; D056931:Cryptochromes; D004268:DNA-Binding Proteins / Q000378:metabolism; D029721:Drosophila Proteins; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005420:Flavoproteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins; D017956:Photoreceptor Cells, Invertebrate; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D050976:Basic-Leucine Zipper Transcription Factors; D015415:Biomarkers; D056926:CLOCK Proteins; D056931:Cryptochromes; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D005136:Eye Proteins; D005420:Flavoproteins; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D011506:Proteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D015534:Trans-Activators; D014157:Transcription Factors; C538960:BMAL1 protein, human; C538963:CRY1 protein, human; C538966:CRY2 protein, human; C538965:Cry1 protein, rat; C538968:Cry2 protein, rat; C485975:DBP protein, rat; C490671:HLF protein, human; C539022:PER1 protein, human; C512644:PER3 protein, human; C539024:Per1 protein, rat; C512646:Per3 protein, rat; C489490:TEF protein, human; C119828:cry protein, Drosophila; C071247:Tef protein, rat; C095828:Hlf protein, rat; C538943:CLOCK protein, human; C538945:Clock protein, rat