Circadian Disruption and the Molecular Clock in Atherosclerosis and Hypertension

Abstract

Circadian rhythms are crucial for maintaining vascular function and disruption of these rhythms are associated with negative health outcomes including cardiovascular disease and hypertension. Circadian rhythms are regulated by the central clock within the suprachiasmatic nucleus of the hypothalamus and peripheral clocks located in nearly every cell type in the body, including cells within the heart and vasculature. In this review, we summarize the most recent preclinical and clinical research linking circadian disruption, with a focus on molecular circadian clock mechanisms, in atherosclerosis and hypertension. Furthermore, we provide insight into potential future chronotherapeutics for hypertension and vascular disease. A better understanding of the influence of daily rhythms in behaviour, such as sleep/wake cycles, feeding, and physical activity, as well as the endogenous circadian system on cardiovascular risk will help pave the way for targeted approaches in atherosclerosis and hypertension treatment/prevention.

Figure 1.

Core components of the molecular clock. A transcription-translation feedback loop involving transcription factors BMAL1 and CLOCK that bind to E-box response elements within promoter regions of target genes, including PER1/2/3, CRY1/2, REV-ERBα/β, RORα/β, DBP, TEF, and HLF (positive arm). Once translated, PER and CRY dimerize and translocate back into the nucleus inhibiting BMAL1/CLOCK to repress their own transcription (negative arm). ROR activate BMAL1 and NFIL3 transcription via interaction with ROR response elements, whereas REV-ERB inhibit BMAL1 and NFIL3 (secondary loop). DBP, TEF, and HLF interact with D-box response elements to activate PER1/2/3, REV-ERBα/β, and RORα/β transcription, whereas NFIL3 represses this (tertiary loop). Created with Biorender.

Figure 2.

Circadian misalignment and disruption in the molecular clock function have potential negative impacts on cardiovascular risk. Circadian rhythms are important for vascular function and subsequently, blood pressure control. Studies in humans and rodents suggest circadian misalignment, through shift work, abnormal light exposure, poor sleep, and aging, and disruption in the molecular clock function (e.g. clock gene mutation) can increase the likelihood of atherosclerosis and hypertension. There are several clinical trials ongoing investigating whether chronotherapeutic interventions, including light and sleep therapy, are beneficial for treatment of hypertension and cardiovascular disease. Created with Biorender.