Molecular clock mechanisms and circadian rhythms intrinsic to the heart.

Circadian rhythms are the external expression of an internal clock mechanism that measures daily time.1 Periodic environmental cues entrain or set the circadian clocks. The daily light-dark cycle represents the most dominant and potent entraining stimulus in mammals. An entrained clock coordinates physiological events to the 24hour day. Normally, cardiovascular or hemodynamic parameters, such as heart rate and blood pressure, exhibit variations consistent with circadian rhythm. Additionally, several types of acute pathological cardiac events exhibit circadian or at least diurnal rhythm patterns. Specifically, the incidences of acute myocardial infarction, myocardial ischemia, out-ofhospital cardiac arrest, ventricular tachycardia, postmyocardial infarction, and sudden death in heart failure all vary according to the time of day.2–5 Also, diurnal rhythms can influence degree and form of cardiac hypertrophy and remodeling.6,7 For instance, the degree of nocturnal blood pressure elevation in patients with systemic hypertension correlates with the severity and concentricity of left ventricular hypertrophy.8,9 Investigators postulate that these circadian or diurnal variations depend on centrally mediated autonomic or neurohumoral activation. However, peak incidence for some acute events, such as sudden death, does not temporally correspond to the circadian sympathetic activation. Thus, alternative inputs or mechanisms for these rhythm patterns have been postulated. Regardless of the input, the intrinsic clock mechanism must respond and regulate some of the circadian rhythms within the heart itself. The intrinsic response elements for the putative external circadian inputs had not until recently been identified or characterized in the heart.10,11 Circadian rhythms are controlled by a transcriptional feedback system fluctuating as a function of the light-dark cycle. Molecular control of a circadian clock mechanism has been described in detail in the fruit fly.12 Similarities between the core clock mechanisms in fruit flies and mice occur with both exhibiting interlocking positive and negative transcriptional and translational feedback loops.1,10 Molecular clock mechanisms have been identified in the suprachiasmatic nuclei comprising the master circadian clock mechanism in the mammalian brain. This master clock presumably sets the phase for intrinsic molecular clocks identified in peripheral tissues including heart.1,10,11 The negative-feedback loop of the molecular clock mechanism involves dynamic regulation of three Period genes, designated Per 1–3 in rats and mice and two cryptochrome genes (cry 1–2).10,11 Two key transcription factors forming a heterodimer, CLOCK and BMAL1, regulate the rhythmic transcription for the mammalian Per and Cry genes (see review by Reppert and Weaver1). After PER and CRY translation, these proteins form a variety of multimeric complexes that are translocated into the nucleus. The CRY proteins act as negative regulators by directly interacting with CLOCK and/or BMAL1 and inhibiting transcriptional activation by the BMAL1-CLOCK heterodimer. Concurrently, PER2 enhances bmal1 transcription, which is the phase opposite to Per/cry, and initiates the positive-feedback loop. The BMAL1-CLOCK heterodimer binds to cis-acting elements in the promoter region for multiple target genes including Per, cry, and bmal1. A delay of 6 hours between peak gene and peak protein expression contributes to the phasic nature of the positiveand negative-feedback loops.13 The circadian rhythm for the genes involved in the intrinsic molecular clock has recently been confirmed and characterized in the rat heart.11 Posttranscriptional regulation of the specific transcription factors, such as CLOCK:BMAL1, still requires detailing, including confirmation that changes in protein expression follows the phasic changes in gene expression. The circadian rhythm of the molecular clock presumably enables the heart to adapt to various physiological stimuli, which change during the day. Thus, the response of the targets for the transcriptional factors involved in regulation of the clock requires determination. Furthermore, characterization of the relationship between intrinsic circadian rhythms and adaptation of the heart to chronic stress might elucidate disease process mechanisms.11 A study in this issue of Circulation Research14 follows previous work11 by the same investigative group in defining intrinsic circadian rhythms in heart. Previously, Young et al11 demonstrated that the rhythm of major genes involved in the clock mechanism was not disturbed in a rat model of myocardial hypertrophy, induced by aortic banding. However, rhythm changes were blunted for various clock output or target genes including PAR (rich in proline and amino acid residues) transcription factors dbp (albumin D-element binding protein), hlf (hepatic leukocyte factor), and tef (thyrotrophic embryonic factor). These data led to the hypothesis that the heart with pressure overload–induced hypertrophy loses The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Division of Cardiology, Department of Pediatrics, University of Washington, and Children’s Hospital and Regional Medical Center, Seattle, Wash. Correspondence to Michael A. Portman, MD, Department of Cardiology, Children’s Hospital and Regional Medical Center, 4800 Sand Point Way NE, PO Box 5371/CH-11, Seattle, WA 98105-0371. E-mail [email protected] (Circ Res. 2001;89:1084-1086.) © 2001 American Heart Association, Inc.