Abstract 4369001: Circadian Disruption by Shift Work Drives Aortic Valve Calcification Through BMAL1-SEMA6D-PPARγ Axis Inhibition

Background: Calcific aortic valve disease (CAVD) is a leading cause of heart failure and cardiovascular mortality worldwide. While disruption of circadian rhythm by means of shift work has been associated with cardiovascular disease in humans, its role in CAVD remains unclear. Objective: To explore the correlation between shift work and CAVD, elucidate the mechanism of circadian rhythm disruption caused by shift work in promoting aortic valve calcification, and discover new strategies for the treatment of CAVD. Methods and results: The cohort study including 263 910 participants without valvular heart disease at baseline in the UK Biobank demonstrated that shift work exposure was associated with a higher risk of aortic stenosis (AS) [hazard ratio (HR) 1.21, 95% confidence interval (Cl) 1.06-1.38]. ApoE -/- mice were exposed to either regular light-dark cycles or weekly alternating light-dark cycles (12 hours shifts), as a well-established model for shift work. After 24-week high fat diet feeding, more severe aortic valve calcification was observed in mice exposed to alternating light-dark cycles, with increased transvalvular flow velocity, thickened valve leaflets, and elevated collagen fiber and calcium deposition within the valves. Alternate of the light-dark cycle disrupted the expression of circadian clock genes, particularly leading to downregulation of Bmal1 (brain and muscle Arnt-like protein 1). Genetic knockout of Bmal1 in mice markedly exacerbated aortic valve calcification, which was not influenced by light conditions. In parallel, silencing of BMAL1 promoted osteogenic differentiation of human aortic valve interstitial cells. Mechanistically, BMAL1 functioned as a transcription factor driving SEMA6D expression. Under the influence of downregulation of BMAL1 expression, the BMAL1-SEMA6D-PPARγ axis was inhibited, which promoted the progression of aortic valve calcification. Besides, SR8278 restored BMAL1 expression, attenuating calcification in vivo and inhibiting TNF-α-induced osteogenesis in vitro. Conclusion: Shift work exposure is associated with increased AS risk. Activation of TNF signaling pathway and downregulation of BMAL1 expression promotes aortic valve calcification by inhibiting the BMAL1-SEMA6D- PPARγ axis under weekly alternating light-dark cycles. The BMAL1 agonist SR8278 may serve as a potential adjuvant therapy for CAVD. Keywords: Calcific aortic valve disease, Circadian rhythm, shift work, TNF signaling, BMAL1