Review article
Circadian clock-mediated regulation of blood pressure

https://doi.org/10.1016/j.freeradbiomed.2017.11.024Get rights and content

Highlights

  • Maintaining normal circadian rhythms in BP is critical for cardiovascular survival.

  • Circadian clock proteins are master regulators of gene expression in most tissues.

  • Clock proteins function in every tissue that contributes to BP regulation.

  • Clock-mediated regulation of target genes underlies circadian rhythms in BP.

Abstract

Most bodily functions vary over the course of a 24 h day. Circadian rhythms in body temperature, sleep-wake cycles, metabolism, and blood pressure (BP) are just a few examples. These circadian rhythms are controlled by the central clock in the suprachiasmatic nucleus (SCN) of the hypothalamus and peripheral clocks located throughout the body. Light and food cues entrain these clocks to the time of day and this synchronicity contributes to the regulation of a variety of physiological processes with effects on overall health. The kidney, brain, nervous system, vasculature, and heart have been identified through the use of mouse models and clinical trials as peripheral clock regulators of BP. The dysregulation of this circadian pattern of BP, with or without hypertension, is associated with increased risk for cardiovascular disease. The mechanism of this dysregulation is unknown and is a growing area of research. In this review, we highlight research of human and mouse circadian models that has provided insight into the roles of these molecular clocks and their effects on physiological functions. Additional tissue-specific studies of the molecular clock mechanism are needed, as well as clinical studies including more diverse populations (different races, female patients, etc.), which will be critical to fully understand the mechanism of circadian regulation of BP. Understanding how these molecular clocks regulate the circadian rhythm of BP is critical in the treatment of circadian BP dysregulation and hypertension.

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.

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