Circadian Disruption and the Molecular Clock in Atherosclerosis and Hypertension.

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.

Adrenal-Specific KO of the Circadian Clock Protein BMAL1 Alters Blood Pressure Rhythm and Timing of Eating Behavior.

Brain and muscle ARNT-like 1 (BMAL1) is a core circadian clock protein and transcription factor that regulates many physiological functions, including blood pressure (BP). Male global Bmal1 knockout (KO) mice exhibit ∼10 mmHg reduction in BP, as well as a blunting of BP rhythm. The mechanisms of how BMAL1 regulates BP remains unclear. The adrenal gland synthesizes hormones, including glucocorticoids and mineralocorticoids, that influence BP rhythm. To determine the role of adrenal BMAL1 on BP regulation, adrenal-specific Bmal1 (ASCre/+ ::Bmal1) KO mice were generated using aldosterone synthase Cre recombinase to KO Bmal1 in the adrenal gland zona glomerulosa. We confirmed the localization and efficacy of the KO of BMAL1 to the zona glomerulosa. Male ASCre/+ ::Bmal1 KO mice displayed a shortened BP and activity period/circadian cycle (typically 24 h) by ∼1 h and delayed peak of BP and activity by ∼2 and 3 h, respectively, compared with littermate Cre- control mice. This difference was only evident when KO mice were in metabolic cages, which acted as a stressor, as serum corticosterone was increased in metabolic cages compared with home cages. AS Cre/+ ::Bmal1 KO mice also displayed altered diurnal variation in serum corticosterone. Furthermore, these mice have altered eating behaviors where they have a blunted night/day ratio of food intake, but no change in overall food consumed compared with controls. Overall, these data suggest that adrenal BMAL1 has a role in the regulation of BP rhythm and eating behaviors.