Abstract 449: Circadian Clock Components Regulate the Thrombotic Response to Injury
Cardiovascular function undergoes diurnal variation, which may be influenced by the master clock in the suprachiasmatic nucleus. Rhythms in genes relevant to vascular integrity and the response to injury exist in mouse aorta and levels of plasminogen activator inhibitor-1 (PAI-1) undergo a diurnal rhythm similar to that in stroke and myocardial infarction in humans. Recently, we exploited mutant mice to implicate the molecular clock in the regulation of blood pressure. Here, we show that clock genes influence the response to a thrombogenic stimulus in vivo. A diurnal variation in the time to thrombotic vascular occlusion (TTVO) subsequent to a photochemical injury was observed in WT mice and this pattern was disrupted with clock dysfunction. TTVO varied significantly from 24.6±2.7min at ZT2 to 40.3±4.3min at ZT8 and 24.3±2.3min at ZT14 (P< 0. 0001). Platelet aggregation responses ex vivo were unaltered, while congruent changes in tissue plasminogen activator and PAI-1 coincided with the thrombogenic response at ZT14, but not at ZT2. Mutation of CLOCK and deletion of NPAS2 abolished diurnal variation in TTVO. Having identified the molecular repertoire of a clock in endothelium, we utilized mice - Bmal1fx/fx-TekCres - in which BMAL1 had been selectively deleted to parse its role in thrombogenesis. Disruption of the endothelial clock modulated the diurnal variation in thrombogenesis but not systemic blood pressure. Key components of the molecular clock regulate the response to a thrombogenic stimulus in vivo and may contribute to the diurnal variation in cardiovascular events observed in humans.