Circadian Medicine: The Role of the Circadian Clock Mechanism in Cardiovascular Health and Disease

Abstract

The circadian system plays a critical role in coordinating daily rhythms in cardiovascular physiology and in molecular pathways regulating cardiac growth, renewal, and remodeling. Conversely, disruption of circadian rhythms has adverse effects on cardiovascular health, influencing both the incidence and progression of cardiovascular disease. In order to translate these findings to improve human health, this thesis investigates emerging approaches applying circadian medicine to target the time-of-day regulation of cardiovascular biology and benefit outcomes in cardiovascular disease. Study 1 demonstrates that short-term pharmacological targeting of the circadian mechanism factor REV-ERB benefits long-term cardiac repair post-myocardial ischemia/reperfusion in mice. Treatment for as little as 1 day post-reperfusion with the REV-ERB agonist SR9009 limits the early activation of the NLRP3 inflammasome, reducing inflammatory cell recruitment, leading to less infarct expansion, and preventing the progression to heart failure. Second, using a circadian genetics approach, Study 2 shows that ClockΔ19/Δ19 mice are protected from heart disease in a model of diet-induced obesity. While both wild type and ClockΔ19/Δ19 mice develop obesity and metabolic dysfunction on a high-fat diet (HFD), in contrast to wild type, ClockΔ19/Δ19 mice are resilient to HFD-induced cardiac transcriptional changes and oxidative stress and are protected from cardiac remodeling and contractile dysfunction. These results demonstrate a novel role for the molecular circadian clock mechanism in resilience to cardiovascular disease. Thirdly, Study 3 uses an approach targeting the circadian environment to investigate the role of rest in heart health and repair. This study establishes a novel mouse model of rest, using light to extend the murine rest period. Using this approach, rest was shown to influence diurnal cardiovascular physiology and regulate the expression of genes important for cardiac growth and renewal. Moreover, rest benefits healing and repair in a mouse model of pressure overload-induced cardiac hypertrophy. Translational investigations demonstrate that rest-responsive genes are conserved in human heart disease, using open-access datasets, and are targets of current front-line cardiac medications. Collectively, this work provides new understanding of the role of the circadian mechanism in cardiac growth, renewal, and remodeling. These studies pioneer new approaches to apply circadian medicine to cardiovascular health and disease.