The circadian clock in cardiovascular regulation and disease: Lessons from the Nobel Prize in Physiology or Medicine 2017

Abstract

The 2017 Nobel Prize in Physiology or Medicine was awarded to Jeffrey Hall, Michael Rosbash, and Michael Young for their discoveries of the molecular circadian clock (Figure 1). The Nobel Laureates 2017. (From left to right): Jeffrey C. Hall, Michael Rosbash, and Michael W. Young. It has long been recognized that organisms adapt their behaviour to a 24-h time cycle. Already in the 18th century the French astronomer Jean-Jacques d’Ortous de Mairan demonstrated the existence of an internal clock through his observations on the mimosa plant, which opens and closes its leaves in a circadian fashion, even when placed in complete darkness. Two hundred years later Ron Konopka and Seymour Benzer (both Nobel-ineligible because they passed away in the past decade) identified fruit flies (Drosophila) with defective 24-h rhythms; these flies all had a mutation in the same gene. In 1984, Jeffrey Hall and Michael Rosbash molecularly characterized this gene called Period (PER).1 They found that PER protein levels oscillated with a 24-h pattern. In 1994, Michael Young discovered a second core clock protein, TIM, encoded by the gene Timeless. 2 This, later supported by discovery of additional clock proteins, such as CLOCK (CLK) and CYCLE (CYC), eventually led the Nobel Prize winners to conclude that a self-sustaining transcription-translation feedback loop governs the 24-h rhythms observed. In this mechanism, PER and TIM proteins accumulate in the cytoplasm, form a heterodimer, and translocate into the nucleus. CLOCK and CYCLE similarly form a heterodimer, activating transcription of particular target genes, including period and timeless. When PER/TIM bind to CLK/CYC, the complex detaches from DNA, thereby terminating transcription of downstream genes. Thus, PER and TIM inhibit their own transcription via CYC and CLK. As PER and TIM protein levels decrease, CYC and CLK are no longer inhibited, allowing reactivation of transcription, such that the loop starts again. Like the clock described in Drosophila, the mammalian circadian clock is a transcriptionally-based cell autonomous mechanism,3 comprised of numerous positive (e.g. BMAL1, CLOCK) and negative (e.g. PER, CRY, REV-ERBα) components (Figure 2). One full ‘revolution’ of the core clock components takes approximately 24 h (slightly shorter in rodents and slightly longer in humans). These clocks, which are found in all mammalian cells, can be broadly divided into peripheral and central clocks, based on anatomical location. The central clock (often termed the ‘master’ clock) is found within the suprachiasmatic nucleus (SCN), a specialized region in the hypothalamus consisting of approximately 10 000 neurons. Peripheral clocks (often termed ‘slave’ clocks) are therefore those located elsewhere in the body, including non-SCN regions of the brain. Clocks must be reset on a routine basis, ensuring synchrony both between the organism and the environment, as well as maintaining internal synchrony (i.e. correct temporal alignment of clocks between different cells/organs). For the central clock, the primary ‘Zeitgeber’ (entrainment factor) is light (signal sent via the retinohypothalamic tract), while peripheral clocks are sensitive to neurohumoral modulation. Problems can therefore arise through circadian disruptive behaviours (e.g. shift work, travel through time zones) and disease states (e.g. obesity, diabetes mellitus), when inappropriate timing of Zeitgebers misaligns circadian clocks, invariably augmenting pathogenesis.4 The molecular circadian clock and cardiology. The molecular circadian clock, of which a simplified version is schematically depicted in the centre, sustains a 24-h rhythm that has impact on several facets of cardiology. Time-of-day-dependent oscillations have been reported for both physiological cardiovascular (CV) regulation (e.g. heart rate, blood pressure) and disease states (e.g. arrhythmia, sudden cardiac death, myocardial infarction). Such observations have been explained classically by fluctuations in neurohumoral factors (e.g. sympathetic tone, cortisol, etc.), secondary to daily behaviours (e.g. sleep-wake and fasting-feeding cycles). However, both human- and animal-based studies suggest that circadian clocks not only drive rhythms in CV physiology and pathology, but they may be an important therapeutic target for disease prevention and/or treatment (Figure 2). For example, 24-h rhythms in specific cardiovascular regulatory mechanisms [e.g. heart rate, norepinephrine, cortisol, plasminogen activator inhibitor (PAI-1), and platelet activation] persist when individuals are forced to lead either a 20- or 28-h day, indicating mediation by an intrinsic circadian system (i.e. clocks). The clock-driven early morning rise in PAI-1 closely parallels increased risk of myocardial infarction at this time. Myocardial injury as assessed by circulating necrosis markers such as troponin I is also increased in patients during the morning hours, a rhythm that appear