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Therapeutic applications of circadian rhythms for the cardiovascular system.

Tsimakouridze EV, Alibhai FJ, Martino TA - Front Pharmacol (2015)

Bottom Line: Over the past decade, the circadian clock mechanism has emerged as a crucial factor regulating these daily fluctuations.Most recently, these studies have led to a growing clinical appreciation that targeting circadian biology offers a novel therapeutic approach toward cardiovascular (and other) diseases.Cardiovascular disease remains a leading cause of death worldwide and new approaches in the management and treatment of heart disease are clearly warranted and can benefit patients clinically.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research Group, Department of Biomedical Sciences, University of Guelph Guelph, ON, Canada.

ABSTRACT
The cardiovascular system exhibits dramatic time-of-day dependent rhythms, for example the diurnal variation of heart rate, blood pressure, and timing of onset of adverse cardiovascular events such as heart attack and sudden cardiac death. Over the past decade, the circadian clock mechanism has emerged as a crucial factor regulating these daily fluctuations. Most recently, these studies have led to a growing clinical appreciation that targeting circadian biology offers a novel therapeutic approach toward cardiovascular (and other) diseases. Here we describe leading-edge therapeutic applications of circadian biology including (1) timing of therapy to maximize efficacy in treating heart disease (chronotherapy); (2) novel biomarkers discovered by testing for genomic, proteomic, metabolomic, or other factors at different times of day and night (chronobiomarkers); and (3) novel pharmacologic compounds that target the circadian mechanism with potential clinical applications (new chronobiology drugs). Cardiovascular disease remains a leading cause of death worldwide and new approaches in the management and treatment of heart disease are clearly warranted and can benefit patients clinically.

No MeSH data available.


Related in: MedlinePlus

The circadian timing system. (A) Light stimulus is relayed by the eye to the suprachiasmatic nucleus in the brain, which in turn synchronizes the heart and other organ clocks to the day and night environment. (B) These signals entrain the molecular clock mechanism, which keeps 24-h time in tissues and cells via transcription-translation feedback loops. BMAL1 and CLOCK are transcribed and translated. BMAL1 and CLOCK heterodimers bind to E-box enhancer elements to promote transcription of cryptochrome (CRY), period (PER), nuclear receptor subfamily 1, group D, member 1/2 (rev-erbα/β; nr1d1/2), and other clock controlled genes (ccg). Proteins CRY and PER are phosphorylated by casein kinase 1δ/𝜀 (CK1δ/𝜀) in the cytoplasm, which translocate to the nucleus to repress CLOCK and BMAL1 mediated transcription. Additional loops exist whereby REV-ERBα/β negatively regulates bmal1 transcription by binding to RRE (REV-ERB/retinoic acid receptor-related orphan receptor (ROR) response element). This mechanism regulates 24-h transcription of clock controlled genes which in play a crucial role in diurnal cardiovascular physiology. (C) Therapeutic applications of circadian rhythms include chronotherapy by timing treatment to daily rhythmic processes, chronobiomarkers of differing rhythmic profiles between health and disease, and new chronobiology drugs targeting the circadian clock mechanism.
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Figure 1: The circadian timing system. (A) Light stimulus is relayed by the eye to the suprachiasmatic nucleus in the brain, which in turn synchronizes the heart and other organ clocks to the day and night environment. (B) These signals entrain the molecular clock mechanism, which keeps 24-h time in tissues and cells via transcription-translation feedback loops. BMAL1 and CLOCK are transcribed and translated. BMAL1 and CLOCK heterodimers bind to E-box enhancer elements to promote transcription of cryptochrome (CRY), period (PER), nuclear receptor subfamily 1, group D, member 1/2 (rev-erbα/β; nr1d1/2), and other clock controlled genes (ccg). Proteins CRY and PER are phosphorylated by casein kinase 1δ/𝜀 (CK1δ/𝜀) in the cytoplasm, which translocate to the nucleus to repress CLOCK and BMAL1 mediated transcription. Additional loops exist whereby REV-ERBα/β negatively regulates bmal1 transcription by binding to RRE (REV-ERB/retinoic acid receptor-related orphan receptor (ROR) response element). This mechanism regulates 24-h transcription of clock controlled genes which in play a crucial role in diurnal cardiovascular physiology. (C) Therapeutic applications of circadian rhythms include chronotherapy by timing treatment to daily rhythmic processes, chronobiomarkers of differing rhythmic profiles between health and disease, and new chronobiology drugs targeting the circadian clock mechanism.

Mentions: The underlying foundation for cardiovascular chronotherapy stems from observations that biological processes in humans (and other mammals) exhibit 24-h daily rhythms, and these are controlled by molecular circadian clocks in the brain, heart, and other organs (Figures 1A,B). There are many excellent reviews on the circadian system (reviewed in Hastings et al., 2003; Roenneberg and Merrow, 2005; Dardente and Cermakian, 2007; Mohawk et al., 2012). Cardiovascular physiology appears to follow a rhythm as well; heart rate (HR), blood pressure (BP), and cardiac contractility all peak in the wake hours and reach a nadir during sleep (reviewed in Martino and Sole, 2009; Durgan and Young, 2010; Paschos and FitzGerald, 2010). Indeed, many cardiovascular functions that oscillate over the 24-h period are influenced by the circadian clock mechanism as well as daily fluctuations in the neurohormonal milieu (reviewed in Bray and Young, 2008; Sole and Martino, 2009; Gamble et al., 2014). Timing of onset of cardiac pathologies also follows a rhythm (e.g., onset of myocardial infarction [MI, or heart attack; Muller et al., 1985), and sudden cardiac death (Muller et al., 1987)]. These time-of-day variations in cardiovascular physiology and pathophysiology have led to a growing clinical appreciation that endogenous circadian rhythms may be an important factor to consider in treating disease. Here, we review the current knowledge regarding therapeutic applications of circadian rhythms for the cardiovascular system (Figure 1C), specifically (1) timing of therapy (chronotherapy), (2) circadian biomarkers (chronobiomarkers), and (3) how modifiers of the circadian clock mechanism may be useful in the treatment of heart disease.


Therapeutic applications of circadian rhythms for the cardiovascular system.

Tsimakouridze EV, Alibhai FJ, Martino TA - Front Pharmacol (2015)

The circadian timing system. (A) Light stimulus is relayed by the eye to the suprachiasmatic nucleus in the brain, which in turn synchronizes the heart and other organ clocks to the day and night environment. (B) These signals entrain the molecular clock mechanism, which keeps 24-h time in tissues and cells via transcription-translation feedback loops. BMAL1 and CLOCK are transcribed and translated. BMAL1 and CLOCK heterodimers bind to E-box enhancer elements to promote transcription of cryptochrome (CRY), period (PER), nuclear receptor subfamily 1, group D, member 1/2 (rev-erbα/β; nr1d1/2), and other clock controlled genes (ccg). Proteins CRY and PER are phosphorylated by casein kinase 1δ/𝜀 (CK1δ/𝜀) in the cytoplasm, which translocate to the nucleus to repress CLOCK and BMAL1 mediated transcription. Additional loops exist whereby REV-ERBα/β negatively regulates bmal1 transcription by binding to RRE (REV-ERB/retinoic acid receptor-related orphan receptor (ROR) response element). This mechanism regulates 24-h transcription of clock controlled genes which in play a crucial role in diurnal cardiovascular physiology. (C) Therapeutic applications of circadian rhythms include chronotherapy by timing treatment to daily rhythmic processes, chronobiomarkers of differing rhythmic profiles between health and disease, and new chronobiology drugs targeting the circadian clock mechanism.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4400861&req=5

Figure 1: The circadian timing system. (A) Light stimulus is relayed by the eye to the suprachiasmatic nucleus in the brain, which in turn synchronizes the heart and other organ clocks to the day and night environment. (B) These signals entrain the molecular clock mechanism, which keeps 24-h time in tissues and cells via transcription-translation feedback loops. BMAL1 and CLOCK are transcribed and translated. BMAL1 and CLOCK heterodimers bind to E-box enhancer elements to promote transcription of cryptochrome (CRY), period (PER), nuclear receptor subfamily 1, group D, member 1/2 (rev-erbα/β; nr1d1/2), and other clock controlled genes (ccg). Proteins CRY and PER are phosphorylated by casein kinase 1δ/𝜀 (CK1δ/𝜀) in the cytoplasm, which translocate to the nucleus to repress CLOCK and BMAL1 mediated transcription. Additional loops exist whereby REV-ERBα/β negatively regulates bmal1 transcription by binding to RRE (REV-ERB/retinoic acid receptor-related orphan receptor (ROR) response element). This mechanism regulates 24-h transcription of clock controlled genes which in play a crucial role in diurnal cardiovascular physiology. (C) Therapeutic applications of circadian rhythms include chronotherapy by timing treatment to daily rhythmic processes, chronobiomarkers of differing rhythmic profiles between health and disease, and new chronobiology drugs targeting the circadian clock mechanism.
Mentions: The underlying foundation for cardiovascular chronotherapy stems from observations that biological processes in humans (and other mammals) exhibit 24-h daily rhythms, and these are controlled by molecular circadian clocks in the brain, heart, and other organs (Figures 1A,B). There are many excellent reviews on the circadian system (reviewed in Hastings et al., 2003; Roenneberg and Merrow, 2005; Dardente and Cermakian, 2007; Mohawk et al., 2012). Cardiovascular physiology appears to follow a rhythm as well; heart rate (HR), blood pressure (BP), and cardiac contractility all peak in the wake hours and reach a nadir during sleep (reviewed in Martino and Sole, 2009; Durgan and Young, 2010; Paschos and FitzGerald, 2010). Indeed, many cardiovascular functions that oscillate over the 24-h period are influenced by the circadian clock mechanism as well as daily fluctuations in the neurohormonal milieu (reviewed in Bray and Young, 2008; Sole and Martino, 2009; Gamble et al., 2014). Timing of onset of cardiac pathologies also follows a rhythm (e.g., onset of myocardial infarction [MI, or heart attack; Muller et al., 1985), and sudden cardiac death (Muller et al., 1987)]. These time-of-day variations in cardiovascular physiology and pathophysiology have led to a growing clinical appreciation that endogenous circadian rhythms may be an important factor to consider in treating disease. Here, we review the current knowledge regarding therapeutic applications of circadian rhythms for the cardiovascular system (Figure 1C), specifically (1) timing of therapy (chronotherapy), (2) circadian biomarkers (chronobiomarkers), and (3) how modifiers of the circadian clock mechanism may be useful in the treatment of heart disease.

Bottom Line: Over the past decade, the circadian clock mechanism has emerged as a crucial factor regulating these daily fluctuations.Most recently, these studies have led to a growing clinical appreciation that targeting circadian biology offers a novel therapeutic approach toward cardiovascular (and other) diseases.Cardiovascular disease remains a leading cause of death worldwide and new approaches in the management and treatment of heart disease are clearly warranted and can benefit patients clinically.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research Group, Department of Biomedical Sciences, University of Guelph Guelph, ON, Canada.

ABSTRACT
The cardiovascular system exhibits dramatic time-of-day dependent rhythms, for example the diurnal variation of heart rate, blood pressure, and timing of onset of adverse cardiovascular events such as heart attack and sudden cardiac death. Over the past decade, the circadian clock mechanism has emerged as a crucial factor regulating these daily fluctuations. Most recently, these studies have led to a growing clinical appreciation that targeting circadian biology offers a novel therapeutic approach toward cardiovascular (and other) diseases. Here we describe leading-edge therapeutic applications of circadian biology including (1) timing of therapy to maximize efficacy in treating heart disease (chronotherapy); (2) novel biomarkers discovered by testing for genomic, proteomic, metabolomic, or other factors at different times of day and night (chronobiomarkers); and (3) novel pharmacologic compounds that target the circadian mechanism with potential clinical applications (new chronobiology drugs). Cardiovascular disease remains a leading cause of death worldwide and new approaches in the management and treatment of heart disease are clearly warranted and can benefit patients clinically.

No MeSH data available.


Related in: MedlinePlus