doi: 10.1161/01.RES.0000214331.90904.aa
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© 2006 American Heart Association, Inc.
Editorials |
How Senescent Vascular Cells Lose Their Clock Age-Dependent Impairment of Circadian Rhythmicity in Smooth Muscle Cells
From the Laboratorio di Biologia Vascolare e Terapia Genica (B.I.), Centro Cardiologico Fondazione "I. Monzino", IRCCS, Milan; and the Laboratorio di Patologia Vascolare (C.G., M.C.C.), Istituto Dermopatico dell’ Immacolata, IRCCS, Rome, Italy.
Correspondence to Dr Maurizio C. Capogrossi, Direttore del Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’Immacolata, Via dei Monti di Creta 104, 00167 Rome, Italy. E-mail capogrossi{at}idi.it
See related article, pages 532–539
Key Words: senescence • gene expression • chromatin • circadian rhythm • cardiovascular
"Oh dear! Oh dear! I shall be too late!"— —Alice’s Adventures in Wonderland, Lewis Carroll
In mammals, as well as in flies and even in prokaryotes, circadian rhythmicity is allowed by a genetic clockwork that tightly regulates organisms’ adaptation to daily variations of light, temperature, and other living conditions.1 The master pacemaker of the hierarchically organized cell-autonomous circadian clocks2 is localized in the densely packed 2x104 neurons of the hypothalamic suprachiasmatic nuclei (SCN), which is reset mainly by light signals captured by the retina. Although clocks resident in peripheral tissues, the so-called peripheral clocks, are mainly controlled by the SCN, an abrupt change in feeding time synchronizes these clocks independently of the central clock.3 In fact exogenous (eg, light) or endogenous rhythms can temporally adjust the cellular clocks, whose main characteristics are (1) feedback regulation and (2) 24 hours oscillatory period.
At molecular level, circadian rhythms are maintained by the intracellular feedback loop of the clock genes.4 The principal members of this family are the mPer 1 and 2 genes,5 Brain and Muscle RNA-t-like protein (BMAL-1),6 Clock,7 the 2 Cryptochrome genes (mCry1 and 2),8 Casein Kinase I
(CKI),9 and the orphan receptor Rev-erb
.10 These genes constitute a well-conserved transcritpion/translation-based negative feedback loop. In mammals, Clock and BMAL-1 proteins are in the positive limb of the loop, whereas mPERs and Cryptochromes are in the negative.2,11 Clock/BMAL-1 heterodimeric complex, associated to the histone acetyltransferase p300,12 bind to an E-box motif in the promoters of Per and Cry genes, allowing their transcription. Per and Cry protein products translocate from the cytoplasm to the nucleus, acting as negative regulators of Clock/BMAL-1 complex, repressing their own transcription. Further, BMAL-1 gene transcription is negatively regulated by REV-erb, whose transcription is activated by Clock/BMAL-1.13 This mechanism accounts for the circadian oscillation of Bmal-1 expression which is in antiphase with Per expression. Besides this transcription/translation-based oscillatory mechanism, which is common to central and peripheral clocks,14 posttranslational modifications of clock gene products, such as phosphorylation and ubiquitination, modulate their stability and/or function.15,16
Aging alters mammalian circadian rhythms by a disregulation of clock genes expression17 and the work of Kunieda et al18 in this issue of Circulation Research, gives new insights about the molecular mechanisms underlying the loss of circadian rhythmicity in senescent cells, with particular emphasis on vascular human smooth muscle cells (HSMCs). Although it has been demonstrated that the peripheral clock is responsive to a variety of stimuli and some molecular mechanisms have been already elucidated,19,20 no information were available about the modification of the oscillatory rhythms in aged vascular cells. The authors clearly demonstrate an attenuation of clock genes expression in senescent HSMCs compared with the young counterpart, which is related, at least in part, to telomeres shortening and impaired CREB activation. In fact, either prevention of telomere shortening or the restoration of CREB activity overcome the impairment of circadian rhythmicity in senescent HSMCs. Moreover, as already demonstrated in other cellular systems,21 the authors describe a correlation between CREB activation and clock genes expression, providing novel data regarding a direct involvement of CREB in the maintenance of BMAL-1 circadian oscillations.
SCN rhythmic transcription of Per1 and 2 gene depends on histone acetylation/deacetylation waves occurring in their promoter regions22 (see Figure, panel A). Chromatin acetylation is required for vascular specific gene expression23,24 and histone acetyltransferases for the chromatin remodelling of vascular clock genes promoter in a circadian time–dependent manner.25 Is the impairment of circadian expression of clock genes in senescent HSMCs paralleled by the loss of acetylation/deacetylation waves in their promoter regions? And if so, is this phenomenon dependent on an inappropriate recruitment of transcriptional complexes onto the chromatin? Is the chromatin of senescent vascular cells less accessible to the circadian transcriptional machinery? The answer to these fundamental questions could indicate, perhaps, temporally modified histones as a reasonable therapeutic target for age-associated pathologies characterized by an impairment of circadian rhythms.
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In the attempt to dissect the signal transduction pathway responsible for the decreased circadian response in senescent HSMCs, Kunieda et al ascribed a pivotal role to extracellular signal-regulated kinase (ERK) (see Figure, panel B). Indeed, ERK activation is lower in senescent HSMCs compared with young cells. Because it has been demonstrated the nitric oxide–cyclic guanosine monophosphate (NO/cGMP) pathway is important for the circadian responses to light in the SCN in vivo26 and given the essential role of NO in the vascular system, whose ability to produce NO declines with age,27 it would be of interest to investigate whether in aged HSMCs a disregulated response to NO may account, at least in part, for the impaired signaling and circadian oscillation of clock genes expression.
Finally, the authors have demonstrated that senescence inhibits circadian oscillation of clock genes in vivo. In transplantation experiments, in which fat tissue from young and old mice was implanted into young recipient, they showed a decreased clock gene expression in the fat tissue from old mice, reporting also an impairment of Per2 and Bmal-1 expression in the old hearts. These results may explain the higher susceptibility of aged hearts to myocardial ischemia, because vascular clock genes have been suggested as unique players of a novel molecular mechanism of the morning onset of myocardial infarction.28
Disregulation of clock genes have been shown to occur in several diseases, including diabetes29 and cancer.30 The search for molecular therapeutic targets for age-associated pathologies cannot exclude clock genes, because an alteration of the endogenous day/light cycle is one feature of aging. Kunieda and coworkers propose in their study the regulation of the ERK/CREB pathway as a therapeutic strategy to counteract age-associated impairment of circadian rhythms. However, before a circadian clock-based therapeutic approach may be suitable, the high complexity of the genetic clockwork and the absence of specifically targeted drugs should be taken into account. Future studies addressing the role of posttranslational modification of clock proteins15,16 and histones22,25 should integrate the current paucity of information about this system and provide a better elucidation of peripheral clocks response to specific stimuli.19,20
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Acknowledgments |
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We thank Dr Antonella Farsetti, from the Neurobiology and Molecular Medicine Institute, CNR, Rome, Italy, for critical reading of the manuscript.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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Related Article:
Circ. Res. 2006 98: 532-539.
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