Review articleCircadian clock-mediated regulation of blood pressure
Graphical abstract
Introduction
The circadian clock evolved in order for organisms to better adapt to the 24 h cycles of light/dark that occur on our planet. Circadian rhythms in physiological function have been identified in organisms ranging from cyanobacteria to humans. In higher eukaryotes and mammals, a central clock resides in the suprachiasmatic nucleus (SCN) of the brain and is directly entrained by light. Peripheral clocks are present in other areas of the brain and in most other cell types and tissues throughout the body. These clocks are synchronized in response to food and light cues and communicate via hormonal and neuronal signals. Desynchronization of the circadian system, such as what may occur in shift work or chronic jet lag, is associated with increased risk for a number of negative health outcomes. For an excellent review on this topic, please see Buijs et al. [1].
The core molecular components of the circadian clock are a group of transcription factors that regulate gene expression [2]. These transcription factors function in a series of feedback loops that drive circadian gene expression for the core clock genes and an extensive number of target genes. In mammals, BMAL1 and CLOCK comprise the positive loop of the circadian mechanism in which they drive expression of the Period and Cryptochrome genes (encoding PER1-3, CRY1 and 2), and the Ror and Nr1d1/2 genes that encode the nuclear receptors ROR and REV-ERB (RORα-γ, REV-ERBα and β). In the negative feedback loops, PER and CRY antagonize BMAL1/CLOCK action. ROR and REV-ERB feedback on and mediate opposing action on BMAL1 gene expression. This transcriptional mechanism is regulated post-translationally through the action of key circadian kinases such as CK1δ/ε, and protein turnover is affected by FBXL family members leading to proteasome-mediated degradation. For an excellent and detailed review by recent Nobel Prize winner Dr. Michael Young on the molecular mechanisms of the clock, including new insights revealed by structural biology analysis of clock proteins, see [3].
Indeed, nearly 50% of all expressed genes throughout the entire body are subject to this mechanism of circadian regulation [4]. In a given tissue, 10–15% of genes are likely to be regulated by this molecular circadian clock, and the target genes of the clock vary in a tissue-specific manner. For example, the clock mechanism has been linked to regulation of ion transport genes in the kidney and metabolic pathway genes in the liver [5], [6]. We now know that the circadian clock components function in every cell type and tissue. This mechanism likely underlies the established daily variations in most physiological functions, including sleep/wake patterns, respiration, metabolism, body temperature, and blood pressure (BP). Circadian regulation of BP is an especially important topic. Although it is well-established that loss of the normal circadian rhythm of BP is associated with adverse cardiovascular outcomes, the mechanism of this effect is not understood. Moreover, evaluation of BP rhythms in humans is woefully underperformed. The purpose of this review is to consider the wealth of evidence supporting a role for the molecular clock in the regulation of BP. Here we review evidence from humans and rodent models that has lent considerable insight into the regulatory mechanisms and importance of circadian rhythms in BP control.
Section snippets
Blood pressure regulation
It has been known for several decades that BP exhibits a circadian rhythm in humans. BP dips at night during rest, undergoes a steep increase in the morning (known as the “morning surge”), and peaks typically in the late afternoon. This circadian rhythm of BP is present in the mouse and rat models that are commonly used to model human cardiovascular physiology.
BP is the product of cardiac output (CO) and total peripheral resistance (TPR): BP = CO × TPR. BP is the measure of the force that blood
Circadian blood pressure disorders in humans
Both SBP and DBP have a circadian rhythm that repeats every 24 h in healthy humans. Healthy individuals experience a 10–20% decrease in BP at night. People who do not exhibit this “dip” of at least a 10% change in resting BP are termed “non-dippers.” Non-dipping hypertension is associated with activation of the renin-angiotensin-aldosterone system (RAAS) [8], increased risk of chronic kidney disease [9], [10] and adverse cardiovascular events [11], [12], [13], [14]. The combination of
Mechanisms of circadian BP regulation in humans
It is well-established that the sympathetic nervous system contributes to the morning surge in BP [32], [33]. Early studies in humans aimed at studying 24 h of BP patterns focused on postural effects and concluded that the central nervous system likely controlled the rhythmicity of BP and other cardiovascular parameters [34] which is corroborated by subsequent studies [35]. For example, in a small study with 9 human subjects with essential hypertension but normal dipping patterns, Sowers found
Blood pressure phenotypes in rodent models
Convincing evidence from numerous animal studies clearly demonstrates an important role for the molecular clock in the regulation of blood pressure. Indeed, every clock gene mutant or knockout mouse that has been tested exhibited a blood pressure phenotype [55]. Below we review these mouse studies and consider the underlying mechanism of the BP phenotype. See Table 1 for a summary.
BMAL1. Curtis et al. generated global Bmal1 KO male C57Bl/6 mice, which exhibited significantly lower BP compared
Chronotherapy and clinical implications
Hypertension is the primary risk factor for cardiovascular disease (CVD), the leading cause of death of Americans. More than one-third of adults in the U.S., approximately 80 million people, are hypertensive and the American Heart Association predicts that this will increase to more than 40% of the population by 2030 [81]. Despite the availability of several classes of anti-hypertensive agents, more than half of high-risk patients do not have adequate BP control [82]. Undoubtedly, this
Free radical biology and circadian BP regulation
Little information is available regarding the connection between free radical biology and regulation of BP by the molecular circadian clock. There is ample evidence however demonstrating that redox signaling is closely linked with the circadian clock mechanism. Indeed, Rodrigo and Herbert have written a compelling review article in this issue focusing on vascular function and BP in relation to circadian variations in redox signaling [102]. One area that is likely to provide clues to how redox
Acknowledgements
This work was supported by NIH DK109570, AHA Grant-in-aid, and NIH AG052861 to MLG and T32DK104721 to LGD.
References (104)
- et al.
Reversed circadian blood pressure rhythm independently predicts endstage renal failure in non-insulin-dependent diabetes mellitus subjects
J. Diabetes Complicat.
(1999) - et al.
The trouble with circadian clock dysfunction: multiple deleterious effects on the brain and body
Neurosci. Biobehav. Rev.
(2014) - et al.
Consequences of circadian disruption on cardiometabolic health
Sleep Med. Clin.
(2015) - et al.
Night-shift work and cardiovascular risk among employees of a public university
Revista da Associacao Medica Brasileira
(2012) - et al.
Cardiac clocks and preclinical translation
Heart Fail Clin.
(2017) - et al.
Relationships of vascular function with measures of ambulatory blood pressure variation
Atherosclerosis
(2014) - et al.
The complex relationship between CKD and ambulatory blood pressure patterns
Adv. Chronic Kidney Dis.
(2015) - et al.
Determinants of circadian blood pressure rhythm in essential hypertension
Am. J. Hypertens.
(1999) - et al.
Model of robust induction of glomerulosclerosis in mice: importance of genetic background
Kidney Int.
(2003) - et al.
Regulation of alphaENaC expression by the circadian clock protein Period 1 in mpkCCD(c14) cells
Biochim. Biophys. Acta
(2010)