Cardiovascular disease, chronopharmacotherapy, and the molecular clock

Advanced Drug Delivery Reviews 62 (2010) 956–966

Contents lists available at ScienceDirect

Advanced Drug Delivery Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a d d r

Cardiovascular disease, chronopharmacotherapy, and the molecular clock☆ Norihiko Takeda a, Koji Maemura b,⁎ a b

Division of Biology, University of California, San Diego 9500 Gilman Dr. La Jolla, CA 92093, USA Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan

a r t i c l e

i n f o

Article history: Received 8 December 2009 Accepted 28 April 2010 Available online 6 May 2010 Keywords: Myocardial infarction Endothelial function Thromboembolism Hypertension Heart failure Peripheral clock Arrhythmia

a b s t r a c t Cardiovascular functions such as heart rate and blood pressure show 24 h variation. The incidence of cardiovascular diseases including acute myocardial infarction and arrhythmia also exhibits diurnal variation. The center of this circadian clock is located in the suprachiasmatic nucleus in the hypothalamus. However, recent findings revealed that each organ, including cardiovascular tissues, has its own internal clock, which has been termed a peripheral clock. The functional roles played by peripheral clocks have been reported recently. Since the peripheral clock is considered to play considerable roles in the processes of cardiac tissues, the identification of genes specifically regulated by this clock will provide insights into its role in the pathogenesis of cardiovascular disorders. In addition, the discovery of small compounds that modulate the peripheral clock will help to establish chronotherapeutic approaches. Understanding the biological relevance of the peripheral clock will provide novel approaches to the prevention and treatment of cardiovascular diseases. © 2010 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . Molecular clock in mammalian cells . . . . . . . . . . . . . . Molecular/peripheral clocks in cardiovascular organs . . . . . . 3.1. The peripheral clock in endothelial cells . . . . . . . . . 3.2. The peripheral clock in vascular smooth muscle cells. . . 3.3. The peripheral clock in cardiomyocytes . . . . . . . . . 4. Loss of synchronization and disease progression . . . . . . . . 5. Circadian rhythm and chronotherapy in cardiovascular diseases . 5.1. Blood pressure/hypertension . . . . . . . . . . . . . . 5.2. Acute myocardial infarction/pulmonary embolism . . . . 5.3. Arrhythmia . . . . . . . . . . . . . . . . . . . . . . 6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Cardiovascular functions such as heart rate (HR) and blood pressure (BP) show 24 h variation. The incidence of cardiovascular diseases such as acute myocardial infarction, strokes and arrhythmia

☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “ChronoDrug-Delivery Focused on Biological Clock: Intra- and Inter-Individual Variability of Molecular Clock”. ⁎ Corresponding author. Tel.: +81 95 819 7286, +81 95 819 7290. E-mail address: [email protected] (K. Maemura). 0169-409X/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2010.04.011

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also exhibits clear diurnal oscillation (Table 1). Since most of these disorders can induce fatal or severe outcomes, it is important to elucidate the precise mechanism of the onset of these diseases. This circadian occurrence is believed to be tightly associated with an internal clock. In this article, we review the role of the internal clock in the pathogenesis of cardiac diseases and discuss chronotherapeutic approaches. The center of the circadian clock is located exclusively in the suprachiasmatic nucleus (SCN) in the hypothalamus [1]. However, analysis of gene expression in peripheral organs revealed that clock genes are expressed and oscillate with a circadian rhythm in each

N. Takeda, K. Maemura / Advanced Drug Delivery Reviews 62 (2010) 956–966 Table 1 Common onset time of cardiovascular diseases. Diseases

Common onset time

Ref

Atrial fibrillation Ventricular tachycardia/fibrillation Acute coronary syndrome (AMI, uAP, sudden death) Pulmonary embolism Cerebral infarction Subarachinoidal hemorrhage

Morning/night Morning Early morning

[130–132] [139,140] [87]

Early morning Morning Daytime

[86] [144,145] [146]

organ or cell, suggesting that each organ has its own internal clock. This clock system is termed a peripheral clock in comparison with the central clock in the SCN. The central clock within the SCN is believed to affect diurnal rhythm of physical function through regulating autonomic nervous system, rest–activity cycle and a peripheral clock in each organ. The basic mechanism of the peripheral clock is believed to be similar to that of the central clock [2,3]. The central clock in the SCN synchronizes each peripheral clock system coordinately by neurohumoral factors or other unknown pathways (Fig. 1) [4]. The phase of peripheral clock can be reset or entrained by a certain external stimuli. Zeitgebers (timekeepers) are defined as factors that reset or entrain rhythm. Light is one of the main zeitgebers in the central clock in the SCN, whereas the peripheral clock in each tissue is not entrained by light. Thus, circadian phases in the peripheral tissues must be synchronized by neuronal and other factors from the SCN. Before establishing chronotherapeutic approaches, we must elucidate the role of the peripheral clock in each organ and identify appropriate zeitgebers that modulate the phase of each peripheral organ. 2. Molecular clock in mammalian cells The molecular mechanisms of the circadian clock have been examined extensively [1,4–6]. The circadian clock is composed of several positive and negative transcriptional feedback loops. Proteins comprising the core feedback loops of the mammalian molecular clock include three period proteins (PER1, PER2, and PER3), two cryptochrome proteins (CRY1 and CRY2), CLOCK, NPAS2 and two BMAL (BMAL1 and BMAL2) proteins (Fig. 2). Most of these are members of the basic helix-loop-helix (bHLH)/per-arnt-sim (PAS) domain transcription factor family. In mammals, CLOCK and BMAL1 form a heterodimer and bind to CACGTG type E-box elements, which

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exist upstream of the promoters of the per and cry gene, and enhance the transcription of these genes [5]. The PER protein forms a complex with the CRY protein, and inhibits CLOCK/BMAL1-mediated transcription of the per and cry genes resulting in the formation of the core negative feedback loop. In addition to the core feedback loop formed by CLOCK, BMAL1, PER and CRY, there exists another negative feedback loop in the mammalian circadian clock. This loop comprises the bHLH domain containing the transcription factors, deleted in esophageal cancer (dec1, dec2). The heterodimer of CLOCK and BMAL1 also binds to the E-box upstream of dec1 and dec2, thus augmenting their transcriptional activities. Once translated, DEC protein translocates into the nucleus and impairs the transcriptional activity of CLOCK/BMAL1, generating another negative feedback loop. Like DEC proteins, the nuclear receptor REV-ERBα is under the direct transcriptional control of CLOCK/BMAL1 heterodimer. The REV-ERBα protein represses bmal1 transcription, thus, inducing the oscillation of bmal1 gene expression. The heterodimer of CLOCK/BMAL1 activates not only the transcription of per or cry gene, but also many other genes, called clock controlled genes (CCGs). These CCGs, such as arginine vasopressin (AVP) or wee1, are considered to mediate the body's clock function and account for the circadian rhythmicity of many physiological processes, including hormonal synthesis and metabolism. The CCGs also include three proline- and acid-rich (PAR) basic leucine zipper (bZip) transcription factors, D-element binding proteins (dbp), hepatic leukemia factor (hlf), and thyrotrophic embryonic factor (tef) [6]. PAR transcription factors also upregulate the expression of CCGs and, therefore, act as mediators of CLOCK/BMAL1-induced CCG expression. The induction of CCG expression was antagonized by another bHLH transcription factor, E4BP4, which is upregulated by REV-ERBα. The expression of the three PAR transcription factors is antiphase to that of E4BP4. Thus, the balance between PAR and E4BP4 coordinately induces circadian expression of CCGs.

3. Molecular/peripheral clocks in cardiovascular organs In addition to the central clock in SCN, clock genes are known to be expressed in a circadian fashion in peripheral tissues including cardiovascular tissues [7]. Gene expression analysis has demonstrated a rhythmic expression of clock genes in the heart, aorta and kidney [8,9]. Approximately 8–10% of the expressed genes in heart and liver have been reported to have circadian expression, most of which are

Fig. 1. The center of the biological clock is located in the suprachiasmatic nucleus (SCN) in the hypothalamus. In addition, each organ or tissue, such as heart, lung, liver and aorta shows a circadian expression of clock genes. Thus, these clock systems are called peripheral clocks compared to the central clock in the SCN. The circadian outputs of clock controlled genes are, in part, regulated directly by the central clock in the SCN. However, the peripheral clock within each organ is also activated and synchronized by the central clock, resulting in the regulation of the circadian expression of clock controlled genes.

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Fig. 2. CLOCK and BMAL1 form a heterodimer and transactivate the promoters of period (Per) and cryptochrome (Cry), orphan nuclear receptor Rev-erbα, and dec 1 and 2. PER protein accumulates in the cytoplasm, and translocates into the nucleus where it forms a complex with CRY proteins, followed by the inhibition CLOCK-BMAL1-dependent transcription. In contrast, Rev-erbα protein accumulates quickly and inhibits BMAL1 transcription. The heterodimer of CLOCK and BMAL1 also activates the transcription of DEC 1 and 2, inhibiting the transactivation of CLOCK and BMAL1, and establishing a interlocking loop. The CLOCK and BMAL1 heterodimer regulates the transcript levels of target genes, termed clock controlled genes (CCGs), resulting in behavioral and physiological rhythms. The heterodimer also transactivates proline- and acid-rich basic leucine zipper transcription factors, dbp, hlf and tef. These transcription factors, in turn, control the expression of output genes of the oscillator (CCGs).

specific to each organ [10], suggesting that each peripheral clock has organ specific roles. Therefore, it is important to identify tissue or celltype specific target genes of the peripheral clock. We have to emphasize that most evidence about the roles of circadian clock in cardiovascular function has been obtained from rodent studies, but not from human. The roles of endogeneous and exogeneous factors in cardiovascular function seem to be different between rodents and humans, therefore more human studies are required to determine the roles of circadian clocks in human cardiovascular diseases.

3.1. The peripheral clock in endothelial cells Balsalobre et al. have shown the existence of a peripheral clock in each cell using in vitro cultured fibroblasts [2]. They treated fibroblasts with 50% serum for a short time, and found that this stimulus elicits the circadian oscillation of clock genes in fibroblasts. To determine whether each cell in cardiovascular tissues possesses an intrinsic circadian rhythm, we must examine clock gene expression in in vitro cultured cells including vascular endothelial cells, vascular smooth muscle cells and cardiomyocytes. Previously, we analyzed clock gene expression in vascular endothelial cells, and confirmed the presence of circadian regulation of clock gene expression [11]. We also observed that thrombomodulin (TM), a membrane protein with anti-coagulant effect, showed circadian expression. TM expression was directly regulated by the core clock genes, CLOCK and BMAL. Studies from human subjects or rats have already shown that endothelium-dependent vasodilatory function is rhythmic [12,13]. In addition, several groups have demonstrated the role of the clock system in endothelial functions. Viswambharan et al. reported that mice with a Per2 mutation exhibited impaired endotheliumdependent relaxation in response to acetylcholine [14]. They observed a decreased production of nitric oxide and vasodilatory prostaglandins, and an increased release of cyclooxygenase-1-derived vasoconstrictors. Anea et al., using vascular injury models including arterial ligation, intraluminal wire injury and isometric tension analysis in Bmal1-KO and Clockmut mice, observed pronounced endothelial dysfunction with loss of vascular adaptation and predisposition to thrombus in these mutant animals [15]. Akt and subsequent nitric

oxide signaling were significantly attenuated in arteries from Bmal1knockout mice. Wang et al. demonstrated that endothelial cells from Per2 mutant mice exhibit greater senescence together with activated Akt signaling and impaired angiogenesis in a hind-limb ischemia model [16]. Per2 mutant mice show an altered endothelial progenitor cell (EPC) mobilization function. Compared with wild-type bone marrow transplantation mice, EPC mobilization was impaired in Per2 mutant bone marrow transplantation mice in response to ischemia or VEGF stimulation. Bone marrow transplantation or the infusion of wild-type EPC restored blood flow recovery and prevented autoamputation in Per2 mutant mice. 3.2. The peripheral clock in vascular smooth muscle cells Vascular smooth muscle cells also have an intrinsic clock system, and circadian clock gene expression was induced by serum shock, angiotensin II (AngII) or retinoic acid [9,17]. These findings suggest that AngII and retinoic acid function as zeitgebers in this circadian loop. Chalmers et al. searched for the target genes of the peripheral clock in a smooth muscle cell line (Movas-1), and identified that the tissue inhibitor of metalloproteinase 1 and 3, collagen 3a1, transgelin1 (sm22α) and calponin1 showed circadian expression in smooth muscle cells [18]. Kunieda et al. examined the circadian clock system in detail in relation to senescence [19]. They observed an attenuation of the expression of clock genes in senescent human smooth muscle cells (HSMC). The loss of circadian rhythmicity in senescent cells seems to be related to telomere shortening and reduced cAMP response elementbinding protein (CREB) activation. Introduction of telomerase or restoration of CREB activity completely prevented this reduction of clock gene expression associated with senescence. Their study suggested that regulation of the ERK/CREB pathway has a potential to become a therapeutic strategy to counteract age-associated impairment of circadian rhythms. 3.3. The peripheral clock in cardiomyocytes The existence of a peripheral clock in cardiomyocytes was confirmed by Durgal et al. They found that, in addition to serum shock,

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norepinephrine, the sympathetic neurotransmitter, functions as a zeitgeber and influences the timing of the circadian clock within cardiomyocytes [20]. Pyruvate dehydrogenase kinase isozyme (PDK-4) and uncoupling protein-3 (ucp-3) gene were shown to have circadian expression in vivo and in vitro. Most of the studies regarding circadian clock gene expression have been performed using rodents. However, Leibetseder et al. have confirmed rhythmic expression of circadian clock gene components in human hearts [21]. They demonstrated that per1, per2 and bmal1 mRNA in human heart tissue showed clear circadian expression with antiphase to those in rodents. Previous studies demonstrated that glucose transporters 1 and 4 (GLUT-1, 4), muscle-specific glycogen synthase, PDK-4 and atrial natriuretic peptide (ANP) show circadian expression in rat heart tissues [22,23]. The transcript levels of the potassium channels, Kv1.5 and Kv4.2, also indicate apparent circadian fluctuation [24]. The circadian expression of potassium channels may be associated with the diurnal onset of cardiac arrhythmia. Results suggest that potential target genes or their functions in heart tissues, however, are not specific to cardiomyocytes. Therefore, in order to examine cardiomyocyte specific clock function, Young et al. generated a mouse model with an altered clock gene that was expressed specifically in cardiomyocytes. The mice are termed Cardiomyocyte-specified Clock Mutant (CCM) mice [25]. Clock rhythms other than that of the cardiomyocyte are normal in CCM mice. Durgan et al. have identified several metabolic gens as being regulated by the circadian clock within the cardiomyocyte. These include PDK4, UCP3, and genes influencing lipolysis (adiponutrin (ADPN)) and lipogenesis (diacylglycerol acyltransferase 2 (DGAT2)) [25]. Importantly, circadian oscillations in these metabolic genes are abolished in hearts from CCM mice, suggesting that these genes are regulated by cardiomyocyte clock function. To further investigate the target genes of the circadian clock in cardiomyocytes, Bray et al. performed a microarray analysis using wild-type vs. CCM hearts. They identified 548 and 176 genes as being potentially regulated by the peripheral clock within the atrial and ventricular cardiomyocyte, respectively [26]. Among them, genes involved in lipogenesis (1-acylglycerol-3-phosphate O-ocyltransferase) and lipid binding protein (s3-12) showed circadian expression in wild hearts, but were chronically suppressed in CCM hearts. These data suggest that the peripheral clock within the cardiomyocyte likely influences myocardial triglyceride metabolism by regulating genes involved in lipogenesis and lipolysis [25,26]. In agreement with these findings, wild-type hearts exhibit a diurnal variation of triglyceride synthesis in ex vivo hearts, with a peak at the middle of the active phase. However, this diurnal variations are absent in CCM hearts [27]. Young et al. performed a series of comprehensive studies regarding the role of the cardiomyocyte peripheral clock in fatty acid metabolism. Fatty acids are the primary fuel (approximately 70%) utilized by the heart [28]. However, when in excess, fatty acid depresses the contractile function of the heart, through channeling into so-called non-oxidative ‘lipotoxic’ pathways [27,29]. The heart responds to an acute increase in fatty acid by activating both oxidative (mitochondrial β-oxidation) and non-oxidative (TG synthesis or lipotoxic pathway) fatty acid metabolism. Therefore, the heart can attenuate cellular toxicity induced by fatty acid load. Circulating fatty acid and lipid levels exhibit a robust circadian rhythm [30]. The non-oxidative pathway of fatty acid metabolism also exhibits a clear circadian rhythm with increased synthesis of phospholipids, diacylglycerol and triacylglycerol during the light/ sleep phase, a time at which circulating fatty acids are normally high in the rodent. However, mitochondrial β-oxidation rates (oxidation of exogenous oleate, one of the primary monounsaturated fatty acid) do not exhibit a significant circadian rhythm in the ex vivo perfused heart [22,31]. Durgan et al. have found that an acute challenge to the rat heart with elevated fatty acid levels results in the depression of

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cardiac power and efficiency only during the light/sleep phase [31]. A direct challenge of isolated adult rat cardiomyocytes with oleate has no effect on the timing of circadian clock gene oscillations [25]. Based on these findings, the enhanced channeling of fatty acid in nonoxidative lipotoxic pathways during light/sleep phase may induce the susceptibility of fatty acid-induced myocardial depression. In addition to triglyceride synthesis, myocardial glycogen content also exhibits a clear circadian rhythm. Glycogen content in the rat heart increases during the dark/awake phase, and decreases during the light/sleep phase [31]. Bray et al. compared glucose metabolism (glucose oxidation and lactate release) between wild-type and CCM hearts. Under basal conditions, no significant differences were observed [26]. However, under the condition with acute increase in workload, CCM hearts exhibited a marked attenuation in glycogenolysis (assessed by lactate release). These results suggest that the circadian clock within the cardiomyocytes regulates myocardial glycogen metabolism. Moreover, CCM mice lack the diurnal variation in cardiac efficiency usually observed in wild-type hearts, although the overall cardiac function of CCM is unchanged compared with wild type. Evidence obtained so far strongly suggests that the circadian clock influences the metabolism of endogenous energy stores (TG and glycogen) within the cardiomyocyte. In addition, a unique study has shown that the expression and subcellular distribution of CLOCK protein were varied in cardiomyocytes depending on the signal or contraction cycle [32]. Therefore, CLOCK protein may function as a sensor of energy status. 4. Loss of synchronization and disease progression An obvious question is whether the internal clock system is impaired in cardiovascular diseases, and, in turn, whether impairment of this molecular mechanism contributes to the pathogenesis of disorders. There are several reports describing the impairment of the peripheral clock in mouse disease models. In the rat heart with pressure-overload hypertrophy, rhythmic expressions of PAR transcription factors (dbp, hlf), as well as anp, were markedly reduced [23]. In streptozotocin-induced diabetic rats, the phase of circadian rhythm of all components of the clock genes in the heart (bmal1, per2 and hlf) is shifted (approximately 3 h early) [33]. Ischemia/reperfusion (I/R) of the myocardium affects the circadian clock within the ischemic region of the heart compared with that of the non-ischemic region. Circadian clock gene oscillations were rapidly attenuated in the I/R region, whereas they were not affected at the nonischemic region. E4BP4 is known to antagonize the transcriptional activity of PAR family members, such as DBP, HLF and TEF. Induction of E4BP4 at both the gene and protein levels was observed following a myocardial infarction together with a rapid repression of pdk4 and ucp3 expression [34]. In addition, aging or hypertension has been shown to affect the internal circadian rhythm [35,36]. Several elegant studies have analyzed the roles of impaired circadian rhythm in the pathogenesis of cardiovascular diseases. Studies using cardiomyopathic hamsters revealed that repeated phase shifts in the Light/Dark (L/D) cycle and disruption of rhythmicity strongly affected and shortened longevity [37,38]. Martino et al. used a murine model of pressure-overload cardiac hypertrophy (transverse aortic constriction (TAC)) [39]. They kept the mice in a rhythmdisruptive 20-hour (LD 10:10) or normal 24-hour (LD 12:12) environment after TAC surgery. Rhythm-disturbed TAC mice exhibited a complete disruption of locomoter activity and could not consolidate the rhythm. Echocardiography reveals increased left ventricular end-systolic and diastolic dimensions with reduced contractility in rhythm-disturbed TAC animals. In addition, both perivascular and interstitial fibrosis were increased in rhythmdisrupted mice. Interestingly, phenotypic rescue occurred when the external rhythm was normalized to 24-hour.

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Martino et al. also analyzed hamsters with a heterozygotic point mutation, termed +/tau, in the circadian regulatory gene, casein kinase1ε. The mutant allele reduces the circadian period from 24-hour in wild type to 22-hour with fragmented patterns of behavior in +/tau heterozygotes. They found that these mutant animals died at a younger age with cardiomyopathy, extensive fibrosis and severely impaired myocardial function. Surprisingly, when the mutants were kept under the light cycles appropriate for their genotype (22-hour), their diurnal activity rhythms were normalized, and cardiac pathology was reversed with normal function. Moreover, mutants with SCN ablation at a young age did not develop cardiac hypertrophy. These results suggest that it is not the disruption of the peripheral clock, but desynchrony between the external and internal clock, or between the central and peripheral clock that elicits cardiovascular disease. In the +/tau heterozygotes, the peripheral clock is produced not only by the intrinsic 22-hour clock, but also affected by 24-hour signals form the SCN, which results in the existence of two distance periods. When the central clock is changed to 22-hour by the LD cycle, this desynchrony is absent and cardiovascular disease does not develop. After a SCN lesion, the peripheral clocks are free to operate based on their intrinsic rhythm without receiving signals from SCN, and the cardiovascular phenotype is rescued. These data demonstrate that circadian organization is critical for normal health and longevity in rodents. In addition, the adverse effects on cardiovascular homeostasis were rescued by resynchronization of the rhythms. Failure to harmonize internal and external rhythms or central and peripheral clocks augmented cardiovascular target organ damage, and circadian dysregulation can play an etiological role in the development of cardiac diseases. In healthy subjects, the peripheral clock in the cardiovascular system seems to provide the advantage of anticipation, enabling the organ to prepare for external stimulus (e.g., rise in blood pressure in the morning) such that it can respond rapidly to its environment at an appropriate time of the day. As for mouse cardiomyocytes, the expression of the cardioprotective agent, anp, exhibits circadian variation and peaks in the dark phase. This circadian variation of anp expression seems to protect cardiomyocytes against the circadian increase in BP in the evening. Therefore, the loss of synchronization between the central and peripheral clock may elicit the progression of the disease. Loss of synchronization may also occur among peripheral tissues. For example, in the acute phase of myocardial infarction, the phase of the circadian clock in ischemic cardiomyocytes is distinct from that of non-ischemic cardiomyocytes [34]. This loss of synchronization may exaggerate the incidence of myocardial arrhythmia. Even in normal subjects, the time phases of circadian rhythm in veins vary significantly according to anatomical locations [40]. These findings suggest that loss of synchronization of circadian rhythms between each organ or tissue could occur easily in pathological conditions. Collectively these findings suggest that resynchronization of the cardiomyocyte circadian clock with the environment or within each peripheral organ can be a promising strategy for prevention or treatment of cardiovascular diseases. Additional studies are required to identify the zeitgebers for resynchronizing or resetting the phases of the peripheral clocks. There has been no direct evidence, thus far, supporting that nutrients (glucose or fatty acids) influence the timing of the circadian clock within cardiovascular organs. Neither norepinephrine nor epinephrine appears to modulate the peripheral clock in vivo [41]. However, thiazolidinediones, an agonist of PPARγ, may be a potential tool for synchronizing the peripheral clock, since PPARγ was recently shown to induce BMAL1 expression in cardiovascular organs [42]. 5. Circadian rhythm and chronotherapy in cardiovascular diseases In this section, we discuss the roles of the circadian clock system in the pathogenesis of cardiovascular diseases such as hypertension, acute myocardial infarction (AMI), pulmonary embolism (PE) and arrhythmia. Since the onset of these disorders is known to show diurnal oscillation, it is very important to understand the underlying

mechanisms between the clock system and the pathogenesis of the disorders in order to develop a novel strategy of chronotherapy. 5.1. Blood pressure/hypertension Blood pressure (BP) is well known to exhibit 24 h variation with a peak in the morning. A number of factors influence diurnal variation of BP. They include internal factors such as the autonomic nervous system [43], vasoactive intestinal peptide (VIP) [44], plasma cortisol [45], plasma renin activity [46], aldosterone [47] and plasma atrial natriuretic peptide (ANP) [48]. Both sympathetic activity and the renin–angiotensin–aldosterone axes peak in the early morning hours [43,49]. In addition, BP is affected by a variety of external factors including physical activity, emotional state, meal and sleep/wake routine. These extrinsic stimuli also affect the autonomic nervous system, thus the 24-hour variation in BP is representative of both endogenous diurnal rhythm and exogenous factors. Previously, Janssen et al. examined the role of the circadian clock in the BP rhythm, and demonstrated that a lesion of the rat SCN abolishes the circadian rhythm of BP and heart rate (HR) without affecting the 24-hour cycle of locomoter activities [50]. Recently, more detailed studies using mouse genetic technology provided insight into the role of clock system in BP regulation. Woon et al. performed a genetic association study and demonstrated that single nucleotide polymorphisms within the BMAL1 promoter are associated with hypertension and type 2 diabetes [51]. Global deletion of BMAL1 completely abolished the rhythm of BP, and, in addition, this deletion resulted in a hypotensive phenotype due to reduced production of catecholamines [52]. However, endothelial specific deletion of BMAL1 did not alter the temporal oscillation of BP [53]. Wang et al. revealed a clear circadian expression of PPARγ in the aorta. They also identified that PPARγ binds to the BMAL1 promoter and transactivates it [42]. Endothelial or vascular smooth muscle cell specific PPARγ knockout mice showed reduced BP variation together with diminished catecholamine production. In contrast to healthy subjects, the circadian rhythmicity of BP is impaired in aged subjects. Kunieda et al. showed that circadian clock gene expression is impaired, and endothelial NO synthase activity is reduced in aged animals [54]. Aldosterone is secreted in a diurnal pattern, as it increases during sleep [47]. A recent report by Gumz et al. showed that Per1 is regulated by aldosterone and, in turn, mediates aldosterone activity on the expression of the alpha-subunit of the epithelial sodium channel (αENaC) mRNA [55]. Since αENaC is known to regulate BP, this observation suggests role of a molecular regulator on circadian blood pressure pattern. However, the role of endogeneous circadian clock in human BP variation is still under debate. Kerkhof et al. investigated the BP and HR rhythm under 26 h constant illumination and routine procedure in normotensive human subjects [56]. They identified a significant circadian pattern of HR, however they failed to show 24 h variation of BP. Recent study with human subjects suggests a role of the internal clock in BP control. A forced desynchrony protocol in human subjects performed by Scheer et al. demonstrated that extending the behavioral cycle to 28-hour resulted in mild, but significant hypertension, indicating that circadian derangement may result in hypertension [57]. In normal subjects, the diurnal variations of BP are termed normal dippers, in that the sleep-time mean BP is 10–20% lower than that of the daytime mean BP. The difference of BP between daytime and nighttime is the diurnal/nocturnal BP ratio, defined as 100× (mean diurnal BP − mean nocturnal BP) / mean diurnal BP. Based on this parameter, subjects are classified as non-dippers (diurnal/nocturnal BP ratio b10%), dippers (10–20%), extreme-dippers (N20%) and inverse-dippers or risers (ratio b0%, indicating nocturnal BP is higher than the diurnal mean) [58]. The non-dipper type is reported to be associated with patients with secondary hypertension or with

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endothelial dysfunction [59,60]. However, the precise mechanisms underlying the absence of BP decline during the nocturnal phase remain to be elucidated. A number of studies have analyzed the relationship between diurnal BP pattern and disease susceptibility or progression. Compared with the 24-hour mean BP, nocturnal BP was shown to be the most potent predictor of cardiovascular events [61,62]. Subjects with non-dipper patterns are shown to be associated with elevated risk of a series of cardiovascular diseases, such as left ventricular hypertrophy [63], heart failure, myocardial infarction [64,65], brain stroke [58], albuminuria in the kidney [66,67] and progression to end-stage renal disease [68]. Verdecchia et al. compared the occurrence of adverse cardiovascular events between dipper and non-dipper hypertensive subjects, and reported that non-dipper patients had nearly three times as many cardiovascular events than dipper hypertensives [69]. Ohkubo et al. performed a population-based study at Ohasama city, Japan, and reported that a 5% decrease in the decline of sleep-time systolic BP in hypertensive patients was associated with a 31% increase in the risk of cardiovascular mortality. Surprisingly, nondipper normotensives had a relative hazard ratio of cardiovascular mortality (2.16) similar to that of dipper hypertensives (2.37) [70]. Kario et al. studied the riser BP pattern patients and reported that those with riser BP profile had a significantly increased incidence of both fatal and non-fatal stroke as compared to all the other three groups: dippers, non-dippers and extreme-dippers [71]. These studies indicate that a loss of adequate nocturnal decline in BP results in a significant risk factor of cardiovascular mortality independent from the 24-hour mean BP value. Recently Eguchi et al. reported that besides abnormal diurnal BP variation, night time BP variability was an independent predictor of the future incidence of a cardiovascular event among type 2 diabetes patients [72]. Collectively, these findings suggest that cardiovascular risk may be influenced not only by BP elevation, but also by the pattern or variability of circadian BP rhythm. Therefore, the nighttime BP level and BP rhythm profiles are becoming promising targets for establishing novel therapeutic approaches based on biological rhythm, termed chronotherapy. Chronotherapy attempts to raise the drug concentration in synchrony with the internal circadian rhythm in disease processes or symptoms. In addition, it tries to enhance benefits while attenuating adverse effects of medications [73]. The chronotherapy of hypertension can be approached using a special drug-delivery

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technology or adjusting the timing of conventional medications. Results from a recent study indicate that more than 80% of treated hypertensive patients are taking all their medication in the morning [74]. There have been at least four categorized groups in terms of BP variation within a day, and some of these BP variation profiles are now established as risk factors of cardiovascular disorders. Therefore, it is not proper to treat all hypertensive patients with the same regimens. Each physician is required to understand the BP dipping pattern of each patient and individualize the treatment according to the BP profile in order to normalize it to normal dipper pattern. Regarding the action of each anti-hypertensive drug, Hermida et al. reported an extensive review [75,76]. Some of the calcium channel blockers (CCBs) affect the day/night BP ratio. Nifedipine effectively reduces BP in essential hypertension, however, it exerts larger beneficial effect when dosing at bedtime compared with on awakening [77]. As for β-adrenoceptor antagonists, they reduce the day/night BP ratio only when they are ingested in the morning, and not in the evening [75]. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) also exert significant effects on the day/night BP ratio. Several trials reported that a bedtime administration of the ACE-inhibitor results in a safe and effective means of controlling morning blood pressure in hypertensive patients without inducing excessive reduction nocturnally [78,79]. Administration of ARB at bedtime also effectively controlled BP in essential hypertension patients. Bedtime dosing increased the day/ night ratio of BP compared with dosing on awakening [80]. Recently, Hermida et al. performed an elegant study and revealed that administering the drug at appropriate timing is more important in treating patients with resistant hypertension than changing the drug combination to control BP and revert normal BP pattern [81]. Intriguingly bedtime administration of antihypertensive drug may improve not only BP profiles, but also cardiovascular risk factors including blood glucose, low-density lipoprotein-cholesterol and fibrinogen levels [82]. The potential benefit associated with the normalization of the circadian BP profiles (converting from non-dippers to dippers) is still a matter of debate. A randomized study in 200 hypertensives showed that valsartan treatment at bedtime and not in the morning reduced urinary albumin excretion [83]. This benefit was highly correlated with the nocturnal BP decline and diurnal/nocturnal BP ratio increase. Normalization of circadian BP pattern was also associated with a

Fig. 3. In the early morning, blood pressure and heart rate increase, then augment the oxygen demand of the heart. The vascular tone and blood coagulability also increase in the morning. These increases in oxygen demand and decreases in oxygen supply exaggerate a mismatch of oxygen demand and supply in the morning.

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significant decrease in plasma fibrinogen, which is known to be correlated with vascular events [84]. However, the majority of these studies did not differentiate the impact of nighttime dosing from that of more effective BP control. Therefore, owing to methodological issues, the studies performed thus far do not provide definite conclusions on whether chronotherapy provides greater cardiovascular protection than the conventional morning dosing. One promising study, the MAPEC study, is now being held to investigate the potential decrease in cardiovascular risk by introducing chronotherapy to antihypertensive medication [85]. The final report of this study is forthcoming, although three years of follow-up suggest that an increase in the diurnal/nocturnal BP ratio decreases cardiovascular events.

5.2. Acute myocardial infarction/pulmonary embolism It is well known that AMI or PE frequently occurs in the early morning [86,87]. Thus, elucidating of the mechanisms of circadian variation of these disorders will lead to not only a better understanding of the pathogenesis of AMI or PE, but also to the development of preventive strategies [88]. A number of physiological functions exhibit diurnal variation, including BP, HR, coronary blood flow, platelet function, blood coagulability and fibrinolytic activity [88]. In the early morning, systemic BP and HR increase [89] and augment the oxygen demand of the heart. In addition, the vascular tone of the coronary artery rises and coronary blood flow decreases in the morning [90]. These increases in oxygen demand and decreases in oxygen supply exaggerate a mismatch of oxygen demand and supply in the morning. In addition, platelet function and blood coagulability also increase in the morning together with a reduction in fibrinolytic activity, resulting in a hypercoagulable state that could elicit the morning onset of thromboembolic events (Fig. 3). Accumulating evidence suggests that the autonomic nervous system plays a major role in the circadian variation of the onset of AMI. A morning increase in the frequency of ischemic episodes is absent in diabetic patients with autonomic nervous dysfunction [91]. Patients receiving β-blockers do not show morning increases in the incidence of angina, AMI and sudden death [92]. HR variability, which reflects sympathetic/vagal balance, is also associated with the onset of ischemic episodes in chronic stable angina [93]. Platelets are also involved in the variation of AMI or thromboembolic events [94]. Both circulating platelet numbers and their aggregation activity possess circadian oscillation [95,96]. Platelet activation in vivo is induced by catecholamines secreted from the sympathetic nervous system in a circadian fashion. However, studies regarding platelet activation do not show a clear circadian expression of any surface markers characteristic of platelet activation [95]. Therefore, it is unclear whether the internal clock system directly affects the circadian function of platelets. In healthy subjects, activation of the coagulation cascade is accompanied by an increase in fibrinolytic activity, which in turn attenuates the coagulation process and prevents vascular occlusion. Therefore, the balance between these two systems is critical for vascular homeostasis. A high plasma concentration of factor VII is known as a risk factor of death from coronary artery disease [97], and factor VII levels fluctuate with a diurnal variation [98]. In addition, fibrinogen, prothrombin, factor VIII and tissue factor pathway inhibitor, a direct inhibitor of the FXa/TF/FVIIa complex, exhibit circadian activation [99]. Endothelial microparticles are known to induce tissue factor driven coagulation [100]. Madden et al. showed that vascular cell adhesion molecule-1 (VCAM-1) positive microparticle numbers in human blood showed a significant circadian rhythm with a peak at 9 am [101]. These results clearly demonstrated the presence of hypercoagulability in the morning hours.

In contrast, the plasmin–plasmin inhibitor complex, a marker of intravascular plasmin generation, decreases in the morning, resulting in hypofibrinolysis in the morning hours [102]. The fibrinolytic function is determined mainly by the level of tissue plasminogen activator inhibitor-1 (PAI-1), which regulates the activity of tissueplasminogen activator (t-PA). High plasma levels of PAI-1 and tPA are a risk for the occurrence of a first AMI [103], illuminating the fundamental role of fibrinolysis in vascular occlusion. The existence of circadian variation of fibrinolytic activity has been shown in both healthy subjects and patients with ischemic heart diseases with a peak in the afternoon and trough in the early morning [104,105]. Because of the morning decrease in fibrinolytic activity, it is more difficult for the tPA therapy to reestablish the patency of occluded coronary artery during AMI treatment in the morning [106]. Importantly, the concentration and activity of PAI-1 showed a circadian oscillation with a peak in the morning, whereas t-PA activity is reduced in the morning [107,108]. Based on these findings, the circadian rhythm of PAI-1 expression is now considered to contribute to the formation of diurnal fibrinolytic functions. Several groups, including our group, have revealed the relationship between the internal clock and circadian PAI-1 activation. We have shown that, in rodents, PAI-1 mRNA levels, as well as its protein levels exhibit striking circadian rhythm in the heart, aorta and kidney with a peak expression in the evening [8,109]. The circadian oscillation pattern of mouse PAI-1 mRNA is antiphase to that of human PAI-1 activity. Since rodents are nocturnal whereas humans are diurnal, the PAI-1 expression in rodents may account for the rhythm in humans having a peak in the morning. We have demonstrated that CLIF/BMAL2 forms a heterodimer with CLOCK and binds to the E-boxes within the PAI-1 promoter and activate it [8]. PAI-1 promoter was also enhanced by CLOCK/BMAL1 [110]. Oishi et al. demonstrated that a ketogenic diet intake induces the phase shift of the peripheral clock gene together with PAI-1 gene expression. This finding also supports the notion that PAI-1 expression is regulated by a peripheral clock [111]. Interestingly, a ketogenic diet increased the level of PAI-1 activity resulting in a hypofibrinolytic status. Recently, Westgate et al. examined the circadian variation of thrombogenic events in vivo [53]. They performed thrombotic vascular occlusion (TTVO) subsequent to a photochemical injury, and observed a diurnal variability in thrombogenicity in vivo in this model system. A mutation of core clock components in the whole animal (Clockmut) resulted in loss of the dynamic pattern in susceptibility to the thrombotic event. More interestingly, even endothelium specific deletion of the BMAL1 gene (BMAL1fx/fxCreTek) dampened circadian oscillation of thrombogenic processes without altering diurnal variation of systemic fibrinolytic activity, including PAI-1 activation. There results suggest that the peripheral clock of the endothelial cells contributes to the prevention of thrombosis in vivo through the mechanisms other than regulating PAI-1 activity. We analyzed the role of the circadian clock in vascular endothelial cells and found that thrombomodulin (TM) is expressed in a circadian fashion in vascular endothelial cells [11]. The phase of variation of TM expression is similar to that of PAI-1, with a peak in the morning. TM exerts an opposite effect on PAI-1 by inhibiting the function of thrombin or activating protein C [112–114]. These findings suggest that TM is protecting the endothelium from the thrombogenic activity induced by PAI-1 through enhancing its expression in a circadian fashion. Further studies are needed to elucidate the role of the circadian expression of TM in cardiovascular diseases. As for the chronotherapy of ischemic heart disease, several medications have been analyzed from the point of their effectiveness. Nitrates, a vasodilator used to alleviate both preload and afterload of the heart, seems to affect the circadian distribution of ischemic heart attack [115–117]. However, there is no clear evidence showing the beneficial effect of chronotherapy in nitrate dosing. As for calcium

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channel blockers (CCBs), various studies have reported different results [118–120]. Overall, whether a CCB has an effect on ischemic events appears to be determined by the time-dependent effect of the drug. In addition, whether the ischemic event was induced by HR dependently strongly affects the effectiveness of CCBs. For example, nifedipine exerted a small effect on ischemic events induced by HR increase, but had a much higher effect on the event without HR changes [118]. A number of studies have shown that β-adrenergic receptor blockers reduce or abolish the morning peak of ischemic events [92,121–123]. However, as is the case with CCBs, the effect of β-adrenergic receptor blockers seems to vary depending on whether the ischemic event is related to an HR increase [118].

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6. Conclusion Diurnal variations exist in the cardiovascular system at multiple levels including gene expression, protein expression and cellular and organ function. Since the internal clock seems to play a role in these cardiac tissues together with exogeneous factors, identification of genes specifically regulated by the circadian clock will provide insights into the role of this molecular mechanism in the cardiovascular system. In addition, the discovery of small compounds that are able to modulate the peripheral clock will help to establish chronotherapeutic approaches. Understanding the biological relevance of the internal clock will provide new insight into the development, prevention and treatment of cardiovascular disorders.

5.3. Arrhythmia Acknowledgment A number of reports demonstrated the presence of circadian variation of cardiac arrhythmia. Portaluppi et al. extensively summarized about this topic [124]. Accumulating evidence suggests that basic electrophysiological parameters have circadian variation. Atrial and ventricular refractory periods are strongly affected by the autonomic nervous system, in that sympathetic activity shortens it and parasympathetic activity elongates the period. Therefore, fluctuations in autonomic nervous system activity within a day can be a major trigger of circadian onset of cardiac arrhythmia. Each parameter of ECG was analyzed as to whether it has a diurnal variation. ECG or holter ECG, AV nodal function, QT interval, R and T wave voltage and QT interval have been shown to exhibit circadian variation [125–129]. As for the onset of cardiac arrhythmia, paroxysmal atrial fibrillation (pAf) is categorized into two types: vagotonic pAf, which usually occurs at night, and adrenergic pAf, which occurs during the daytime [130–132]. There are several reports showing different results in terms of peak period paroxysmal supraventricular tachycardia (PSVT), from morning to midnight [133–135]. However, they are consistent in that it is rare for PSVT to occur during the nighttime. Continuous holter monitoring of ECG revealed a 24-hour variation in the occurrence of ventricular premature beats (VPBs) with a peak between 6 a.m. and noon [136]. Interestingly, the presence of a circadian onset of VPBs depends on left ventricular function. Only patients with a left ventricular ejection fraction greater than 30% have a circadian variation of VPBs [137]. Goldstein et al. identified a clustering of VPBs between 6 and 10 a.m., however, they did not find any relationship between the onset of VPBs and cardiac mortality. Therefore, they concluded that a circadian onset of VPBs is not a predictor of sudden cardiac death [138]. Based on the data using implantable defibrillators, a circadian variation of ventricular tachycardia (VT) or ventricular fibrillation (VF) was demonstrated with a peak onset between 7 and 11 a.m. accompanied by a small secondary peak in the afternoon [139,140]. This diurnal variation of VT/VF was seen in patients with both ischemic and non-ischemic heart diseases [141]. Kong et al. demonstrated that the time of day was the only independent predictor of the ventricular refractory period [142]. The refractory period is shortest in the morning hours together with the highest incidence of sudden cardiac death [143]. In spite of a number of studies revealing circadian onset of cardiac arrhythmia, only a few reports have analyzed the molecular mechanisms of these findings. Yamashita et al. showed that two voltage gated K channels, 1.5 and 4.2, exhibit diurnal variation at both mRNA and protein levels. Circadian oscillations of these channels are associated with diurnal variation in the electrical properties of isolated cardiomyocytes [24]. Unfortunately, few studies have examined the effectiveness of chronotherapies in anti-arrhythmic treatment. Much more study regarding the role of the internal clock in the pathogenesis of cardiac arrhythmia is required to elucidate the underlining mechanisms of arrhythmia.

We acknowledge support for N.T. from the Japanese Society for the Promotion of Science and the Uehara Memorial Foundation. This study was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education Science and Culture, Japan (to K.M. 21390244).

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