Download Peripheral Circadian Clocks in the Vasculature

Peripheral Circadian Clocks in the Vasculature
Dermot F. Reilly, Elizabeth J. Westgate, Garret A. FitzGerald
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Abstract—Living organisms have adapted to the daily rotation of the earth and regular changes in the light environment.
Life forms anticipate environmental transitions, adapt their own physiology, and perform activities at behaviorally
advantageous times during the day. This is achieved by means of endogenous circadian clocks that can be synchronized
to the daily changes in external cues, most notably light and temperature. For many years it was thought that neurons
of the suprachiasmatic nucleus (SCN) uniquely controlled circadian rhythmicity of peripheral tissues via neural and
humoral signals. The cloning and characterization of mammalian clock genes revealed that they are expressed in a
circadian manner throughout the body. It is now accepted that peripheral cells, including those of the cardiovascular
system, contain a circadian clock similar to that in the SCN. Many aspects of cardiovascular physiology are subject to
diurnal variation, and serious adverse cardiovascular events including myocardial infarction, sudden cardiac death, and
stroke occur with a frequency conditioned by time of day. This has raised the possibility that biological responses under
the control of the molecular clock might interact with environmental cues to influence the phenotype of human
cardiovascular disease. (Arterioscler Thromb Vasc Biol. 2007;27:1694-1705.)
Key Words: circadian 䡲 clock 䡲 diurnal 䡲 peripheral 䡲 SCN
C
ircadian rhythms are daily cycles of physiology and
behavior that are driven by an endogenous oscillator
with a period of approximately (circa-) one day (dies).1 The
most obvious circadian rhythm in humans is the cycle of
sleep and wakefulness.2 These cycles are not simply consequences of light perception, but are generated by endogenous
circadian clocks that can adapt the physiology of an organism
to its needs in an anticipatory manner. Their expression
continues (free-runs) when subjects are isolated from the light
cycle, with the oscillator defining predicted day and night,
organizing our behavior and physiology appropriately to
adapt to the contrasting demands encountered throughout the
24-hour period.
Cardiovascular or hemodynamic parameters such as heart
rate, blood pressure, endothelial function, and fibrinolytic
activity exhibit variations consistent with circadian rhythm.
Additionally, several types of acute pathological cardiac
events exhibit diurnal patterns. The incidence of acute myocardial infarction, myocardial ischemia, cardiac arrest, ventricular tachycardia, post myocardial infarction, and sudden
death in heart failure all vary according to the time of day.3,4
Social and commercial pressures such as shift work, which
oppose the temporal circadian order, may be underlying
factors contributing to the incidence of chronic illnesses such
as cardiovascular disease and cancer.5,6 Understanding this
molecular clock and its mechanisms may ultimately allow
treatment of conditions where either the severity of the illness
or therapeutic efficacy exhibit circadian rhythmicity.
Molecular Basis of Circadian Clocks
Circadian rhythms are regulated by three components: (1) the
circadian pacemaker or “clock”, (2) an input mechanism
which allows the clock to be reset by environmental stimuli,
and (3) an output mechanism which regulates physiological
and behavioral processes.7 In mammals, the master circadian
pacemaker is located in the suprachiasmatic nucleus (SCN) of
the hypothalamus. Circadian clocks are a series of self
sustained transcriptional and translational feedback loops,
which have a free running period of ⬇24 hours. These clocks
are intrinsic to the cell, persisting when tissues and cells are
isolated or cultured in vitro.8 Core clock genes have been
identified and characterized in drosophila and rodent models
harboring naturally occurring, chemically induced, and targeted (knockout) mutations and through various comparative
genomic approaches.9 –13 Our current understanding of the
clock architecture consists of 3 negative and 1 positive loop
of transcription, translation, and posttranslational events.
Heterodimers of basic helix-loop-helix/PER-arylhydrocarbon
receptor nuclear translocator (ARNT)-SIM (bHLH/PAS)
transcription factors circadian locomotor output cycles kaput
(CLOCK) and brain and muscle ARNT-like protein-1
(BMAL1, also known as MOP3) drive transcription through
E boxes located within the promoters of various target genes
including period (Per1-3) and cryptochrome (Cry1-2)
genes.1,14 When Per and Cry are translated, they heterodimerize, translocate to the nucleus, and repress Clock/Bmal1mediated transcriptional activity at E boxes (Figure 1).
Increases in Per protein levels are delayed ⬇6 hours relative
Original received March 28, 2007; final version accepted May 16, 2007.
From the Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia.
Correspondence to Garret A FitzGerald, Institute for Translational Medicine and Therapeutics, 153 Johnson Pavilion, School of Medicine, University
of Pennsylvania, Philadelphia, PA 19104. E-mail [email protected]
© 2007 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol. is available at http://www.atvbaha.org
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DOI: 10.1161/ATVBAHA.107.144923
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Figure 1. Overview of transcriptional/
translational feedback loops in the vascular circadian clock. Rhythmic molecular
transcriptional/translational feedback
loops form the basis of the circadian
clock in many tissues including the vasculature. Clock (Clk) and Bmal1 (Bm) are
2 bHLH PAS transcription factors which
heterodimerize and promote transcription
through E box motifs in many core clock
component genes. Period 1 to 3 (Per)
and Cryptochrome 1 to 2 (Cry) transcription/translation is induced in a rhythmic
manner toward the beginning of the
12-hour light period. Rev Erb ␣ (Rev), an
inhibitor of Bmal1 transcription, is similarly
induced through Ebox motifs by the Clock:Bmal1 heterodimer. Hence Bmal1 levels
will decrease whereas Per and Cry levels
rise as the light phase progresses. At the
end of the light phase, the levels of Per
and Cry proteins are at their peak and
Bmal1 is at a low level. The accumulating
Per and Cry proteins (indicated by P and
C diamond shapes) are phosphorylated
by casein kinase I␧ and heterodimerize
to shuttle back into the nucleus from the
cytoplasm and prevent further Clock:Bmal1 driven transcription through E box
elements. Positive regulators of Bmal1
transcription, such as Ror␣ (Ror), facilitate a subsequent rise in Bmal1 levels
and increased Clock:Bmal1-mediated
transcription, thus restarting the cycle.
to their mRNA, and serine phosphorylation plays a critical
role in regulating their ubiquitin mediated degradation.15
Inhibition of Clock/Bmal1 transcription by Per/Cry complexes ultimately decreases their own expression levels resulting in relief of inhibition, thus restarting the cycle. Fbxl3,
a component of a specific ubiquitin ligase complex, was
recently implicated in the proteasome mediated decay of Cry
proteins.16 –18 Additional interacting feedback loops involve
bHLH domain containing transcription factors Dec1, Dec2,19
and Rev-Erb␣.20 Both Dec1/2 and Rev-Erb␣ contain E boxes
in their promoters and are thus transcriptionally regulated by
Clock/Bmal1 heterodimers. On translation of the corresponding proteins, Rev-Erb␣ specifically represses Bmal1 transcription, whereas Dec1/2 are thought to impair Clock/Bmal1
transactivational capacity.19 Bmal1 expression is positively
regulated by Per2 and by Ror-␣ acting through RORE
sequences in the Bmal1 promoter.13 The overall result of
these transcriptional/translational feedback loops is oscillatory expression of clock genes and proteins with a period at
or near 24 hours.
Initial output from the core clock manifests at the level of
altered gene expression. Genes that are directly regulated by
clock components but are not integral components of the
clock are termed clock controlled or output genes. Oscillating
protein expression of these clock output genes is then thought
to occur, thus potentially impacting cell/tissue function in a
rhythmic manner. Clock/Bmal1 heterodimers can bind to
Ebox elements in numerous output genes including members
of the PAR transcription factor family D-element binding
protein (dbp), hepatic leukemia factor (hlf), and thyrotrophic
embryonic factor (tef) as well as vasopressin, wee1, lactate
dehydrogenase A, and prokineticin2. Expression of genes
containing promoter elements RORE or D box elements
known to be involved in the circadian clock could similarly
be regulated in a rhythmic manner.21
Circadian Clocks in the Periphery
As each of the genes comprising the core circadian clock was
identified, their expression was detected outside the SCN.22
Core circadian clock genes are expressed in non-SCN neural
tissues, as well as in peripheral tissues throughout the body
where most exhibit an oscillating circadian pattern of expression. Indeed, even in culture, immortalized rat-1 fibroblasts
and other cell lines show a circadian pattern of expression
after treatment with serum.8,23 The best known exception to
this rule is the testis, which shows constant rather than cyclic
expression of circadian clock genes in multiple animal
species.24 The central clock in the SCN is entrained by light
signals transmitted along the retinohypothalamic tract,
whereas peripheral oscillators are synchronized by various
neurohumoral stimuli25 and food or metabolic cues26 (Figure
2). Metabolic signals from feeding (or perhaps more importantly starving) appear to be dominant cues for peripheral
clocks. It is becoming increasingly apparent that daily me-
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Figure 2. Organization of the central and peripheral molecular clocks. The suprachiasmatic nuclei synchronize peripheral oscillators
including those within the vascular endothelium, smooth muscle, and the heart through a combination of autonomic, behavioral, endocrine, and food related cues. Both the heart and the vasculature (endothelium and the smooth muscle compartments) rhythmically
express the molecular components of the circadian clock. Tissue specific components such as Bmal2 (CLIF) may help mediate tissuespecific circadian patterns of clock controlled gene expression eg, in the endothelium. Clock controlled genes or “outputs” such as
plasminogen activator inhibitor-1 (PAI-1), D site of albumin binding protein (dbp), Glut1, Glut4, or pdk4 can sustain local clockdependent physiologies such as the thrombolytic activity of tissue plasminogen activator, the 24-hour blood pressure pattern, or
circadian variations in heart rate. Thus, the network of local circadian oscillators in vascular tissues could influence clock-dependent
cardiovascular pathologies, including myocardial infarction, ischemia, and stroke. Vascular tissue–specific differences in molecular components, outputs, and their response to synchronizing factors could allow the design of more effective treatments for pathologies that
carry a circadian bias.
tabolism and the circadian cycle are intertwined.27 Circannual
cycles in mammals (eg, hibernation) are similarly known to
influence and be influenced by metabolism.28 –30 It is believed
that the SCN can synchronize peripheral clocks through
neurohumoral stimuli directly and indirectly (eg, feeding
behavior). In peripheral tissues such as the liver, kidney, and
heart, circadian rhythms in RNA abundance are apparent for
each of the Per genes, although the phase of oscillation is
delayed 3 to 9 hours relative to the oscillation in the SCN.22
Oscillations in cultures of peripheral tissues were observed to
dampen more rapidly than SCN cells in vitro, which sustain
rhythms for weeks.25 However, sophisticated luciferase reporter methods have revealed that peripheral oscillators are
capable of self-sustained oscillations for more than 20 cycles
in isolation.31 Phase dispersion of luciferase rhythms were
observed in tissues explanted from SCN lesioned mice.
Hence, signals emanating from the SCN are now thought to
synchronize, rather than sustain rhythms in peripheral oscillators.31,32 Circadian clock genes are expressed in many
organs, and these peripheral oscillators may tailor circadian
responses to tissue-specific alterations in physiological demands, such as might pertain during starving, feeding, or
exercise.
One potential function of a peripheral clock is to regenerate
a weak or dampened SCN signal, thus amplifying the oscillation of the signal in each tissue. Another is to coordinate
locally clock controlled gene expression in each tissue generating an amplified and synchronized rhythm in response to
asynchronous blood borne signals. Several microarray studies
have helped elucidate that 5% to 10% of the transcriptome is
under circadian control in the liver,33,34 the heart,35 the
SCN,34,35 and in the aorta.36 Surprisingly, the complement of
rhythmic genes between tissues differs substantially, with a
very small percentage of clock controlled genes common to
any 2 tissues. Transcripts found to be oscillating in more than
1 tissue tend to be core clock components or transcription
factors (dbp and Rev Erb␣) close to the core loop which
mediates circadian programming.37,38 Recently, a previously
unappreciated requirement for Per1, Per2, and Cry1 in sustaining cellular circadian rhythmicity was established.39 It
appears that intercellular coupling in the SCN acts not only to
synchronize component cellular oscillators but also for robustness against genetic perturbations.
Peripheral oscillators also differ from the SCN in that they
display tissue specific molecular components of the transcriptional feedback loop that sustain rhythmicity. Bmal2 (also
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Figure 3. Accumulation of circadian clock gene transcripts in aortic smooth muscle cells and mouse aorta and heart. In the mouse
aorta and heart, clock gene mRNA transcripts Per2, Bmal1, and dbp display circadian oscillations. Clock and Bmal1 heterodimers drive
transcription of Per2 and dbp by binding to E box consensus sequences in their promoters. The peak in Per2 and dbp expression is
observed around CT36 corresponding to the transition between the light and dark period. Bmal1 expression is driven by ROR␣ acting
at RRE sequences and subsequently repressed by RevErb␣. The peak in Bmal1 expression is observed at CT24 corresponding to the
transition from the dark phase to the light phase. Mouse tissues were harvested in constant darkness. Clock gene mRNA transcripts
similarly display circadian rhythmicity in human and mouse aortic smooth muscle cells after treatment with 50% serum. Oscillation of
the clock output gene dbp in smooth muscle cells is in phase with Per2 with a peak at t⫽24 hour postserum shock in human cells.
Per2 and dbp peak slightly earlier (close to t⫽18 hours) in mouse smooth muscle cells. Expression of Per2, Bmal1, and dbp was
monitored by qPCR.
known as MOP9 or CLIF) expressed in endothelial cell
cultures dimerizes with Clock to drive clock controlled genes
(CCGs).40 Npas2 (also known as MOP4) is a paralogue of
Clock. It is expressed in the forebrain and vasculature and can
also dimerize with Bmal1 and drive gene expression through
E box sequences.23,41 Transcriptional coactivators and histone
acetyltransferases, p300/CBP PCAF, and ACTR associate
with Npas2 and CLOCK to regulate positively clock gene
expression.42 Temporal coactivator recruitment and chromatin remodeling on the relevant promoters permits the mammalian clock to orchestrate circadian gene expression.43,44
Indeed, a recent report suggests Clock has intrinsic histone
acetyltransferase activity.45 However, the relative importance
of Npas2 and Clock to the core loop in many tissues remains
to be determined.46
Circadian Gene Expression in the Vasculature
The diurnal incidence of cardiovascular disease arises from a
complex interplay among local oscillators in the heart,
endothelium, and vascular smooth muscle, their endocrine
interactions, and their regulation by SCN-dependent changes
in autonomic tone, feeding, stress, and energetic demands.
Dramatic oscillations in circadian clock components have
been observed in vascular smooth muscle cells and in mouse
aorta isolated at different times throughout the 24-hour period
(Figure 3). Rhythmic accumulation of transcripts for almost
all of the core clock components have been observed in
murine vascular tissue.23,36,42,47,48 To date, aortic vascular
smooth muscle cells are the most well characterized in vitro
model of the vascular clock. Rhythms in Per1, Per2, Cry1,
Cry2, Bmal1, Clock, Npas2, Rev Erb␣, dbp, and E4bp4 have
been observed in smooth muscle cells in vitro and aortic
tissue ex vivo. Oscillations in Per1/2, Cry1/2 mRNA levels in
the mouse aorta peak during the early circadian night,
whereas Bmal1, Npas2, and Rev Erb␣ peak at the beginning
of circadian day. Smooth muscle cell models show a similar
phase relationship to that seen in vivo. Rhythms in clock gene
mRNA expression have not yet been observed in vivo in
vascular tissues outside the aorta; however, using tissues
cultured from a Per1 luciferase transgenic rat, Davidson et al
demonstrated rhythms in Per1 promoter activity in a wide
variety of arteries and veins.49 The aorta has been the most
widely studied vascular tissue in terms of gene expression in
a circadian context, in part because of its accessibility and
relative ease of isolation; however, it is quite possible that
molecular clocks within venous and arterial vascular beds
may express differing clusters of circadian output genes.
Indeed, within any single vessel, endothelial, smooth muscle
cell, and fibroblasts express widely differing transcriptomes.
It is therefore possible that the complement of genes under
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circadian control may differ between these cell types. Oscillating clock or clock output gene expression has not, so far,
been reported in isolated endothelial cells in vitro. Cultured
NIH3T3 fibroblasts harbor cell-autonomous and selfsustained circadian oscillators with a relatively wide distribution of period length. However, they can be synchronized
transiently by a short treatment with substances that activate
a wide variety of signaling pathways.32 Single cell recordings
and coculture experiments indicated that cultured fibroblasts
do not influence each other’s rhythms to any measurable
degree. However, different tissue explants harvested from the
same SCN-lesioned animal display circadian oscillations with
different phases and period lengths,31 hence intercellular
communication within an organ must be present but may be
lost in culture. It is tempting to speculate that clocks within
different cellular compartments within a blood vessel may
communicate timing information via paracrine signaling.
Previously, the circadian pattern of gene expression in the
thoracic aorta was examined using Affymetrix high density
arrays.36 Circadian expression of ⬇8000 probesets was examined using U74A arrays. Three hundred seven genes
exhibited a circadian pattern of oscillation in mouse aorta,
including those intrinsic to the function of the molecular
clock. In addition, many genes relevant to protein folding,
protein degradation, glucose and lipid metabolism, adipocyte
maturation, vascular integrity, and the response to injury
demonstrated profound circadian oscillation. It is poorly
understood how oscillating gene expression in vascular tissues might contribute to the temporal pattern of cardiovascular disease. Assessing cardiovascular parameters throughout
the circadian day in transgenic mouse models with disrupted
circadian clocks has provided initial information in this
regard.48,50 However, forthcoming studies of mouse models
with tissue restricted dysfunctional molecular clocks51,52 will
allow a greater understanding of the relative contribution of
both systemic cues and these peripheral oscillators to physiology and disease.
The identification of a vascular clock implicates local
tissue-specific events as potential contributors to the temporal
patterning of cardiovascular disease and, as such, may be
amenable to local modulation. The circadian oscillatory
mechanism throughout the tissues of the vasculature is
potentially a target for tissue-specific therapy, independent of
the SCN and other clock mechanisms. Factors which entrain
timing or sustain rhythmicity within the peripheral vascular
clock are potentially avenues of management.
Circadian Gene Expression in the Heart
Oscillations in gene expression in the heart have been
examined extensively in mouse models using both real-time
polymerase chain reaction (PCR) and expression array
analysis.23,35,42,53–57 Genes encoding both core clock components and CCGs, relevant to cardiac function, have
demonstrated dramatic oscillations in heart tissue isolated
at intervals throughout the circadian day. Included in these
oscillating transcripts are genes relevant to carbohydrate
utilization, mitochondrial function, and fatty acid metabolism.58 While numerous studies have provided insight into
rhythmic heart gene expression, we are only now beginning
to understand the impact of the molecular oscillator on
cardiac physiology.35,56,58 – 60 The role of the circadian clock
within the cardiomyocyte may allow for the anticipation of
diurnal variations in workload, substrate availability, or the
energy supply-to-demand ratio.
Circadian variation in cardiac function persists in isolated
heart tissue, highlighting the cell-autonomous function of the
cardiac clock. Indeed, rat hearts in vitro continue to display
circadian variation in contractile function, sustained by a
circadian variation in oxidative metabolism.58 Diurnal variations in oxidative stress tolerance and lipid peroxidation have
also been observed in isolated perfused rat hearts.61 Similarly,
myocytes isolated at different times of the day have displayed
circadian variation in transient outward and steady state
currents ex vivo.62 The observation that rhythmic cardiac
function persists in the absence of external cues (ie, ex vivo)
highlights the importance of this autonomous clock within the
heart in the regulation of rhythmic cardiac physiology. Other
myocardial processes under circadian control likely include
the responsiveness to sympathetic stimulation, electrical
properties, calcium homeostasis, and antioxidant capacity.
Although the circadian clock within the heart drives
cardiac physiology, function of this clock can be disrupted
under pathological conditions. In a model of experimentally
induced cardiac hypertrophy, the core molecular oscillator
continues to cycle, but the amplitude of oscillations in
transcription factors such as dbp are blunted59 and the
circadian cycle of metabolic gene expression is lost. Hence,
the tissue would be less prepared to cope with routine
increases in physiological demand, predisposing it to metabolic crisis. Streptozotocin-induced diabetes in the rat is
another model of contractile dysfunction which alters clock
gene expression in the heart; clock component oscillations
show normal amplitude but are phase advanced by approximately 3 hours in this model.63 Spontaneously hypertensive
rats show a marked increase in the amplitude of daily cardiac
mRNA rhythms of components of the renin-angiotensin
system.64 Thus, the impact of disease states on the cardiac
circadian clock seems to be at the level of both circadian
clock genes as well as clock controlled output genes relevant
to tissue specific functions.
Environmental and Neurohumoral Influences
on Cardiovascular Function
Chronobiologists have long struggled with the question of
whether physiological processes such as the daily rhythms in
cardiovascular parameters, energy metabolism, body temperature, and hormone release are gated simply by the behavioral
sleep/wake and fasting/feeding rhythms or are subject to
independent control by a circadian oscillator. Locomotor
activity rhythms and circadian oscillations in circulating
hormones (eg, norepinephrine, epinephrine) add a layer of
complexity when trying to decipher the relative contribution
of the central (SCN) and peripheral oscillators to circadian
cardiovascular physiology. We now have good evidence in
many species that sleep and wakefulness are affected by the
circadian clock, but we are only beginning to decipher to
what extent rhythms in physiological functions are themselves directly influenced by the molecular clockwork or
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rather are merely reflective of behavioral rhythms. The
existence of a circadian pattern of body temperature, blood
pressure, endothelial function, fibrinolytic function, and circulating hormones has long been known. This section will
focus on blood pressure, whereas endothelial function and the
fibrinolytic system will be discussed in the final section.
Peak blood pressure levels in humans occur during the mid
morning (at about 10:00 AM) then decrease progressively
throughout the remainder of the day to reach a trough value
the following morning at around 3:00 AM.65– 67 A slow but
steady increase in blood pressure is then observed over the
early morning hours before awakening, with an abrupt and
steep increase at approximately 6:00 AM coincident with
arousal and arising from overnight sleep. This morning blood
pressure surge from low nighttime levels to higher daytime
levels continues for 4 to 6 hours after awakening, with a
secondary dip around 2 pm, thus variations in blood pressure
in general tend to reflect the sleep activity cycle. It has been
shown that the rhythms of blood pressure and heart rate are
controlled by an endogenous circadian circulating system in
which the SCN plays an important role in rats.68,69 However,
it is unknown how the circadian information from the SCN is
modulated/processed to regulate the 24-hour rhythm of blood
pressure and heart rate. The amplitude of the diurnal variation
in blood pressure is increased in patients with hypertension
and the oscillation again coincides with the temporal variability in their incidence of acute vascular events, such as
myocardial infarction, sudden cardiac death, and stroke.70,71
A circadian pattern of blood pressure is maintained in
hypertensive patients, although there is an upward shift to the
blood pressure curve throughout the entire 24-hour period
compared with normotensive subjects and the amplitude of
the rhythm may be altered.72 The absence of a normal drop in
systolic blood pressure (known as “nondippers”) from day to
night has been found to be predictive of heart failure, stroke,
and myocardial infarction, as well as sudden death in elderly
patients with hypertension.73–76 Recently, Halberg and colleagues found that chronobiological analysis of human blood
pressure recordings interpreted in the light of reference values
specified by gender and age predicts actual and proxy
outcomes when dipping fails.77
Day to night differences in physical and mental activity are
thought to be major determinants of blood pressure rhythmicity.78 Analysis of blood pressure rhythms in shift workers
revealed an almost complete resynchronization within the
first 24 hours of the shift rotation. This may reflect variation
in sympathetic activity, consistent with the correlation between diurnal variation in plasma catecholamines and blood
pressure and heart rate. Sympathetic activity appears to integrate the major driving factors of temporal variability in blood
pressure, but evidence also indicates a role of the hypothalamicpituitary-adrenal, hypothalamic-pituitary-thyroid, opioid, reninangiotensin-aldosterone, and endothelial vasoregulatory systems, as well as other vasoactive peptides. Many hormones with
established actions on the cardiovascular system such as
arginine vasopressin (AVP), vasoactive intestinal peptide
(VIP), melatonin, somatotropin, insulin, steroids, serotonin,
CRF, corticotropin (ACTH), thyrotropin-releasing hormone
(TRH), and endogenous opioids, show diurnal varia-
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tions.79 – 87 Physical, mental, and pathologic stimuli, which
may drive activation or inhibition of these neuroendocrine
effectors of biologic rhythmicity, may also interfere with the
temporal blood pressure structure. However, the timedependent responsiveness of cardiovascular tissues to such
stimuli may be just as important. Recently, the circadian
blood pressure pattern was examined in Clockmt/mt, Bmal1⫺/⫺,
and Npas2mt/mt mouse models which have disrupted circadian
rhythmicity to varying extents. It was found that genes that
subserve core functions in the molecular clock regulate
differentially enzymes relevant to the synthesis and disposition of catecholamines. This resulted in alterations in blood
pressure, plasma norepinephrine and epinephrine, their diurnal variation, and, surprisingly, their response to immobilization stress.48 It appears that the circadian clock may
influence the vascular response to stress indirectly, by controlling the underlying rhythm of BP on which asynchronous
cues are imposed but also directly by modulating pressor
response, irrespective of timing. Both effects reflect the
observed influence of the clock on sympathoadrenal function,
which is activated in the integrated arousal response and
many of its discrete elements, such as assumption of an
upright posture, exercise, and emotional stress. Clockdependent effects on blood pressure may also interact with
diurnal variation of hemostatic variables, such as plasminogen activator inhibitor (PAI)-1,88 to determine the diurnal
influence of cardiovascular events.
Neurohumoral Factors: Inputs to Peripheral
Circadian Clocks?
Peripheral oscillators are incapable of receiving direct input
from light; therefore, they rely on the master clock to provide
time cues via entrainment signals. Although peripheral oscillators are capable of maintaining rhythmic output without the
master clock (eg, single cells or single organ cultures), daily
entrainment of peripheral oscillators avoids dampening or
desynchronization of these rhythms.31,32 Recent studies using
clock gene reporter systems (eg, Per2 fused to a luciferase
reporter) demonstrated that oscillations could be sustained for
numerous cycles in cultured peripheral tissues. Tissues from
SCN-lesioned mice similarly displayed rhythms when placed
in culture, but significant desynchronization was observed
both within and among SCN lesioned animals.31 Thus, the
hierarchical organization of the circadian system places the
SCN in a role for coordinating and synchronizing the phase of
peripheral oscillations.
The daily cycle of feeding and starvation, indirectly controlled by the SCN via activity rhythms, appears to be a
dominant entrainment signal for peripheral clocks. When
food is available ad libitum, food intake for mice is normally
consolidated to the dark phase, corresponding to the activity
phase for this nocturnal species. However, during a restricted
feeding regime, where food access is restricted to the light
phase, circadian gene expression in the periphery, but importantly, not in the SCN, is inverted by 12 hours.26,89,90 Thus
food intake, which may present as a synchronous or asynchronous cue, is capable of entraining peripheral oscillators.
Although restricted feeding appears to be a dominant entrainment signal for many tissues, the rate at which these various
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oscillators have the capacity to alter phase can vary. There are
many candidate hormones that may act in a more subtle way
to fine tune peripheral rhythms. Npas2, a component of the
molecular oscillator, heterodimerizes with retinoic acid receptors, and ligation of these receptors by retinoic acid phase
shifts Per2 rhythms in mouse aorta and heart.23 Others have
shown that the glucocorticoid analogue, dexamethasone,
phase shifts peripheral clocks in fibroblasts, liver, heart, and
kidney, without influencing the SCN.26,91 Glucocorticoid
hormones have also been demonstrated to inhibit the uncoupling of central and peripheral oscillators that occurs during
restricted feeding.92 Peripheral oscillators in the cardiovascular system are particularly well placed to receive entrainment
signals from circulating hormones and sympathetic innervation. Adrenergic signaling can influence Per1 expression in
cultured cells and tissues slices in culture93 and can initiate
cycling in clock gene expression in cardiomyocytes,53 however the relative impact of adrenergic signaling on peripheral
oscillators in the heart and vasculature in vivo remains to be
determined. Immobilization stress in mice will induce a
substantial physiologically relevant rise in plasma catecholamines and glucocorticoids. However, in a study by
Yamamoto et al, acute physical stress elevated Per1 mRNA
expression in mouse peripheral organs but behavioral
rhythms and molecular rhythms of clock genes in the periphery were unaffected.94
Angiotensin II plays a central role in the regulation of
systemic blood pressure and fluid homeostasis through its
multiple effects on the vasculature, adrenal glands, kidneys,
and brain. These pleiotropic actions are mediated by specific
receptors (AT1 and AT2).95,96 In rats and mice, high concentrations of these receptors are found in the brain, including
within the SCN. However, the significance of this latter
observation is currently unknown. Components of the reninangiotensin system exhibit considerable diurnal variations
and therefore potentially influence blood pressure circadian
rhythms.97–100 Nonaka et al47 have shown that angiotensin II
induces significant oscillations in bmal1, per2, and dbp, in
VSMCs. Overexpression of the renin2 gene in the rat is
associated with a phase delayed or inverted circadian rhythm
of blood pressure, attenuated circadian and photic induction
of c-fos gene in SCN neurons, and attenuated phase shifting
of behavioral and cardiovascular rhythms in response to
light.101–103 Studies in AT2 receptor knockout mice revealed
disrupted circadian rhythms in blood pressure and heart rate
compared with wild type mice.104 These findings raise the
possibility that angiotensin II may contribute to regulation of
cardiovascular circadian function including integration of the
SCN with the peripheral clock in the vasculature.
An elegant study by Guo et al used parabiosis between
intact and SCN-lesioned mice to show that nonneuronal
signals, either hormonal or behavioral, are capable of synchronizing some peripheral tissues but not others.54 Moreover, the rhythmic expression of Per2 mRNA105 and celladhesion molecules106 in circulating peripheral mononuclear
leukocytes, which have no neuronal connections, provides
further evidence for the existence of circulating phase shifters
or inducers of peripheral clocks in vivo. Peripheral oscillations seem to be coordinated both by major entrainment cues
as well as local phase shifting signals. It is likely that
integration of diverse signals resulting from food ingestion,
hormones (possibly SCN driven), or energy homeostasis may
contribute to the entrainment of peripheral clocks and that
these clocks may be entrained by the SCN through diverse
mechanisms.
Circadian Rhythms and Metabolism
It has now been well established, by using restricted feeding
paradigms, that food/metabolic signals can have a profound
influence on the peripheral clock timing at the molecular
level. Although this phenomenon is not yet fully understood,
it serves to highlight the coregulation of circadian rhythms
and metabolism. The SCN controls the phase of peripheral
tissues mainly by imposing a rest/activity cycle, which in turn
determines a daily feeding cycle. In addition, many neuroendocrine and metabolic systems are subject to strong circadian
control. Metabolic genes have featured extensively as rhythmic transcripts in many tissues examined.34 –36,107 One such
examination of the mouse aorta36 showed circadian variations
in genes of relevance to lipid metabolism, energy balance,
adipocyte maturation, the maintenance of vascular integrity,
and the vascular response to injury. Twenty-two genes
relevant to glycolysis, gluconeogenesis, fatty acid synthesis
and degradation, triglyceride mobilization and storage, and
cholesterol biosynthesis exhibited pathway specific coordination subject to circadian variation. Indeed, several pathways
have been identified that might link circadian networks with
both gluconeogenic and lipogenic pathways. Important metabolic nuclear hormone receptors and transcription factors
including SREBP 1a, SREBP 1c, ROR␣, Rev Erb␣, THR,
PPAR␣ show significant circadian expression in numerous
tissues. SREBP 1a and 1c regulate hepatic lipogenesis,108
ROR␣ has been shown to regulate lipid flux, lipogenesis, and
lipid storage in skeletal muscle,109 increased Rev Erb␣ and
THR expression is observed during adipogenesis,110 whereas
PPAR␣ is involved in the regulation of numerous metabolic
processes.111 Regulation of clock genes by the redox state of
nicotinamide adenine dinucleotide cofactors (NAD and
NADP) has been demonstrated in a human neuroblastoma
cell culture system.112 The reduced forms of these cofactors
NADH and NADPH, strongly enhance DNA binding activity
of the Clock:Bmal1 and Clock:Npas2 heterodimers. In contrast, the oxidized form of these redox factors inhibits the
DNA binding by these heterodimers. The regulation by
NADPH in vitro implies that oscillations in metabolic flux
participate in feedback loops with the clock genes. In particular, glycolytic flux results in cytosolic NADH production
and depends on shuttle mechanisms for NADH transport into
the mitochondria. A study by Young et al reported diurnal
variations in myocardial metabolic flux and contractile function.58 Contractile performance, carbohydrate oxidation, and
oxygen consumption in isolated working rat hearts were
greatest in the middle of the night, with little variation in fatty
acid oxidation. In addition, they observed circadian rhythmicity in a variety of genes involved in carbohydrate and fatty
acid metabolism. In the context of the NAD/NADH enhancing Clock/Bmal1 binding to Ebox elements, the variations in
carbohydrate flux demonstrated by Young et al in the intact
Reilly et al
Vascular Clocks and Cardiovascular Disease
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heart could represent an interacting feedback mechanism for
the clock. It is therefore a possibility that abnormalities in
metabolic flux and NADH generation could disrupt or reset
the peripheral clock in the heart.
In studies using Clock mutant and Bmal1⫺/⫺ mice, a
profound role for the clock in the recovery from insulin
induced hypoglycemia and, specifically, in gluconeogenesis
was observed.113 A high-fat diet amplified the diurnal variation in glucose tolerance and insulin sensitivity in a manner
dependent on the molecular clock. Turek et al reported
abnormalities in adipogenesis and metabolism in Clock mutant mice, including a subtle decrease in energy expenditure,
hyperphagia exaggerated in response to a high-fat diet, and
dysregulation of neuropeptides (Ghrelin, Cart, and Orexin)
that regulate energy metabolism.27 However, on an ICR
background, Clock mutant mice develop lipid malabsorption
and hence do not develop obesity.114 The Clock mutant
mouse, which was a triumph of forward genetics,11 is a
dominant mutation which results in deletion of a putative
activation domain and arrhythmicity in constant darkness. A
recently generated Clock⫺/⫺ mouse retains rhythmic activity,
but the question of whether compensation by Npas2 occurs
remains to be definitively addressed.46 Studies of metabolic
phenotypes in Bmal1⫺/⫺ mice are tempered by progressive
arthropathy and an advanced aging phenotype.115,116 No
doubt emerging mouse models with tissue specific dysfunctional clocks will allow a greater understanding of the
contribution of the molecular clock in distinct tissues to
energy balance and metabolic homeostasis. How peripheral
clocks in many tissues including the cardiovascular system
impact the incidence of cardiovascular disease and metabolic
syndrome remains a fertile area of investigation.
mouse fibroblasts in vitro.118 Aberrant cell division in vivo
has been observed in Per2 mutant mice, which have an
increased susceptibility to tumor development on challenge
with ␥-irradiation.117 Although these data provide evidence
for a role of the molecular clock in regulating the cell cycle,
a functional oscillator is not absolutely required for cell
division, as several mouse models of molecular clock dysfunction are viable. Nevertheless, the impact of the molecular
clock on cell division is evident. Future work will likely shed
light on the relative importance of the molecular clock on
proliferative diseases of varying etiology, including cancer,
atherosclerosis, arthritis, and others. Circadian time may also
influence the outcome of coronary interventions such as
angioplasty, where restenosis reflects a dysplastic response to
injury.120
Recent data have also revealed a link between the molecular clock and aging. Mice deficient in BMAL1 display an
early aging phenotype with shortened life spans, sarcopenia,
cataracts, and other signs of early aging.116 Similarly, Per1/
Per2 double mutant mice age prematurely, as characterized
by a drop in fertility and litter size, loss of soft tissues, and
kyphosis.121 Cellular senescence, a marker of cellular aging,
is evident in human vascular tissues122 and may contribute to
the development of vascular disease.123,124 Interestingly,
Kunieda et al showed that cellular senescence impairs circadian rhythmicity in cultured human aortic smooth muscle
cells. In vivo, mouse embryo fibroblasts (MEFs) were capable of entrainment on implantation into mice, whereas senescent MEFs were impaired in this ability.125 Thus, an interaction between the circadian and cell cycles appears to
influence aging at both the cellular and organismal level.
Circadian Rhythms and the Cell Cycle
Chronobiological Implications for
Cardiovascular Therapy
Like many other biological processes relevant to the cardiovascular system, the cell cycle displays circadian rhythmicity.
Key components of the cell cycle, including cyclin A, cyclin
D1, Cdc2, c-myc, and Wee1 have been shown to be under
transcriptional control by the molecular clock.117,118 More
direct evidence for molecular clock regulation of the cell
cycle in vivo stems from the work by Matsuo et al. Progression of the cell cycle through the G2/M transition, but not
S-phase progression, is gated by the molecular clock to
certain times of the day in a partial hepatectomy model of
liver regeneration.119 This circadian gating involves the
clock-controlled gene Wee1, which inactivates the CDC2cyclin B complex required for G2/M transition. Interestingly,
Wee1 shows a significant circadian expression pattern in
vascular smooth muscle cells synchronized in vitro by the
serum shock model (Reilly D, FitzGerald GA, unpublished
observations, 2007). However, it has yet to be determined
whether the vascular clock can influence the timing of cell
proliferation in vascular cells, which may have implications
for angiogenesis and vessel remodeling.
Mouse models of molecular clock dysfunction have provided further evidence for clock control of the cell cycle.
Liver regeneration after partial hepatectomy is retarded in
cryptochrome-deficient mice, 119 whereas mutation of
CLOCK was recently shown to inhibit the proliferation of
Several lines of evidence suggest that an understanding of the
chronobiological implications for cardiovascular therapy may
prove fruitful. Low-dose aspirin appears to reduce blood
pressure, but only if administered in the evening.126 –128 The
mechanism is unknown. Controlled-onset extended-release
(COER) verapamil, a calcium channel blocker, administered
in the evening to blunt the morning surge in blood pressure,
has shown clinical improvement over morning doses of other
antihypertensive drugs. 129 3-hydroxy-3-methylglutaryl
(HMG)-coenzyme A (CoA) reductase, the target of the statin
family of inhibitors, oscillates in its expression,130 whereas
evening administration of these drugs achieves an optimal
reduction in low-density lipoprotein (LDL).131 There is circadian variation in the thrombolytic efficacy of tPA, which is
most effective when administered between noon and midnight.132 Thus, the timing of drug administration can be
altered to improve therapeutic efficacy. Likewise, as has been
shown for chemotherapeutics, appropriately timed drug administration can diminish adverse drug effects.133 Contributing to the chronobiological effects of cardiovascular therapeutics are variations in target expression and also in drug
absorption, distribution, metabolism, and excretion. Diurnal
variation in the pharmacokinetics of several cardiovascular
drugs, such as propranolol, nifedipine, and enalapril, is
1702
Arterioscler Thromb Vasc Biol.
August 2007
apparent.134 Both transporters and P450 isozymes are among
the most oscillatory of transcripts.
Contribution of the Circadian Clock to the
Temporal Incidence of Cardiovascular Disease
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There is a well observed temporal incidence in adverse
cardiovascular (CV) events, including transient myocardial
ischemia,135 myocardial infarction,136 sudden cardiac
death,137 and stroke,138 –140 which occur most frequently in the
early morning hours just after awakening, but also display a
secondary more subtle peak in the late afternoon. Skeptics of
the circadian argument for the temporal incidence of cardiovascular disease raise the objection that the classification of
morning events might be artifactual or biased. In particular,
unwitnessed events, such as sudden cardiac death occurring
during sleep might be falsely attributed to the morning hours,
when the deceased patient is discovered. In addition, the
patient might sleep through the onset of a heart attack, wake
up at 8 AM and report pain. The increased morning onset of
cardiovascular events may also be the result of exogenous
factors, such as assumption of upright posture and initiation
of daily activities, all of which activate the sympathoadrenal
system and other aspects of the stress response. Although
these arguments may be valid, they do not account for the
consistently observed temporal incidence of adverse events.
Several factors involved in the development of cardiovascular disease are temporally modulated. Blood pressure,
endothelial function, vascular tone, lipid metabolism, platelet
and leukocyte reactivity, and fibrinolysis vary with the time
of day. Moreover, core molecular oscillators have been
identified in the heart59 and vascular tissue,36 encompassing
both vascular smooth muscle and endothelial compartments,
and recent evidence has pointed toward a role of molecular
oscillators in regulating cardiovascular physiology.48,141 The
endothelium secretes low levels of tPA along with the platelet
inhibitors, prostacyclin (PGI2), and nitric oxide (NO),142,143
which are also responsible for regulating vascular tone144 and
blood pressure.145 An early morning surge in blood pressure
is accompanied by a decline in endothelial function, as
assessed by flow-mediated vasodilation146 –148; both phenomena coincide with the clinically observed morning peak
incidence in thrombotic events.149 Per2 mutant mice display
decreased endothelium-dependent vasodilation in response to
acetylcholine,141 further implicating the molecular clock in
the regulation of endothelial-dependent vascular function.
The tendency of platelets to aggregate, which can promote
thrombogenesis, has been suggested to show a diurnal pattern
in humans, however aggregometry studies are conflicting and
potentially confounded by artifact. Other mediators of the
hemostatic system display diurnal variation, including coagulation factors (II, VII, X, and tissue factor pathology
inhibitor [TFPI]).150 –152 The morning onset of myocardial
infarction may partly result from circadian variation of
fibrinolytic activity. Fibrinogen, the circulating precursor of
fibrin (a clot stabilizing protein), displays circadian variation
in humans,153 with a peak in the early morning, whereas the
expression of the fibrinogen gene in mouse liver displays 2
peaks, the first of which seems to be regulated by the
molecular clock.154 PAI-1 is the main inhibitor of the plas-
minogen activators, and thus fibrinolytic activity. PAI-1
activity shows a circadian oscillation peaking in the early
morning, and evidence has indicated a role of the molecular
clock components CLOCK, BMAL1, and CLIF (also known
as MOP9 or BMAL2) in driving E-box–mediated PAI-1
transcription subject to inhibition by PER/CRY complexes.155
Thus, numerous mediators of cardiovascular pathology display circadian variation, and evidence for molecular clock
regulation of these mediators is beginning to unfold. The
physiological importance of control by the circadian clock
remains a fertile area of investigation.
Tempora mutantur et mutamur in illis
(The times change and we change with them.)
John Owen.
Disclosures
None.
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Peripheral Circadian Clocks in the Vasculature
Dermot F. Reilly, Elizabeth J. Westgate and Garret A. FitzGerald
Arterioscler Thromb Vasc Biol. 2007;27:1694-1705; originally published online May 31, 2007;
doi: 10.1161/ATVBAHA.107.144923
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