Neurobiology of the circadian clock and its role in cardiovascular disease: Mechanisms, biomarkers, and chronotherapy

Figures

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  Fig. 1. Composition of body-wide clocks via circadian rhythm. The circadian rhythm coordinates body-wide clocks, optimizing physiology for environmental changes. Light signals, detected by specialized retinal cells, reach the suprachiasmatic nucleus (SCN) via the retino-hypothalamic tract (RHT). The SCN then synchronizes peripheral clocks through neural and hormonal pathways. Feeding and exercise also influence circadian rhythms, which regulate various physiological processes including metabolism and immune function. The zoom-in image of SCN shows the neuroanatomical pathway depicting that the light activates retinal neurons, triggering a signal cascade through the RHT to SCN, PVN, brainstem, and spinal cord. This pathway ultimately reaches the pineal gland via the superior cervical ganglion.

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  Fig. 2. Major advancements in circadian research. A schematic representation charting pivotal discoveries and milestones in the field of circadian rhythm studies, spanning over a century of scientific progress and breakthroughs in understanding biological clock mechanisms.

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  Fig. 3. Events in a mammalian molecular clock. The mammalian circadian clock operates through intricate transcriptional-translational feedback loops, cycling approximately every 24 h. At its core, CLOCK or NPAS2 partners with BMAL1, forming heterodimers that bind to E-box elements in gene promoters. This activates transcription of clock-controlled genes, including Per and Cry. As PER and CRY proteins accumulate, they form complexes that inhibit their own transcription, completing the negative feedback loop. An auxiliary loop involves ROR and REV-ERB proteins, which regulate Bmal1 expression. Additionally, the clock controls NAD + biosynthesis through NAMPT, influencing SIRT1 activity and further modulating clock gene expression. This complex system allows for tissue-specific variations in circadian gene expression patterns.

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  Fig. 4. Circadian regulation of cardiac function. The cardiomyocyte core molecular clock, entrained by external cues, operates autonomously. BMAL1 and CLOCK heterodimerize, initiating expression of REV-ERB, PER1-3, and CRY1-2, which suppress BMAL1 and CLOCK, creating rhythmic oscillations. These transcription factors modulate output genes affecting cardiac contractility, electrophysiology, metabolism, and repair. The diagram illustrates key components and pathways, including AKT, GSK-3β, PIK3R1, SCN, SNS, T3, VGCC, and VIP, demonstrating the complex interplay between the circadian clock and cardiac function.

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  Fig. 5. Sex-specific circadian rhythm variations in cardiovascular system in health and diseases. (A) A 24-h timeline illustrating chronotypes, with arrows indicating later chronotypes for males and earlier for females. (B) The core circadian clock is regulated by a set of genes, including Bmal1, Clock, Cry, and Per. These genes form a feedback loop that drives the circadian rhythm. Recent studies have shown that these genes are not only essential for maintaining circadian homeostasis but also play a role in sex-specific gene expression in the heart. For instance, (a) Bmal1 has been identified as a key factor in conferring sex-specific differences in cardiac gene expression. Hearts from female mice exhibit more rhythmically expressed genes (REGs) compared to male hearts, and the loss of Bmal1 in cardiomyocytes diminishes these sex-specific differences. (b) Estrogen receptors are present in various tissues, including the heart, and have been shown to regulate the expression of clock genes. For example, estrogen has been found to modulate the expression of Per2 and Bmal1 in the heart, suggesting a mechanism by which estrogen influences circadian rhythms in a sex-specific manner. (c) The…