Deficiency of Bmal1 disrupts the diurnal rhythm of haemostasis

Background: Mice deficient in the circadian clock gene BMAL1 (Brain and Muscle ARNT-like protein-1) exhibit a hypercoagulable state and an enhanced arterial and venous thrombogenicity, which aggravates with age. We investigated the effect of BMAL1 deficiency in mice at a different age on the diurnal rhythm of factors involved in coagulation and fibrinolysis. Materials and methods: Hepatic, cardiac and brain tissues were isolated from 10- and 25-weeks-old Bmal1-deficient (BMAL1(-/-)) and wild-type (BMAL1(+/+)) mice at ZT2 and at ZT14 to analyze the mRNA expression level of genes involved in coagulation and fibrinolysis. Results: Body weight and brain weight were significantly lower in all BMAL1(-/-) versus BMAL1(+/+) mice. Bmall deficiency disturbed the diurnal rhythm of plasminogen activator inhibitor-1 (PAI-1) in liver and plasma, but not in cardiac or brain tissues. BMAL1(+/+) livers showed diurnal fluctuations in factor (F)VII, EVIL, protein S and antithrombin gene expression, which were not observed in BMAL1(-/-) tissues. Interestingly, tissue plasminogen activator (t-PA) expression was significantly upregulated in all BMAL1(-/-) versus BMAL1(+/+) brains at both time points. Plasma t-PA-PAI-1 complex levels were however similar for all groups. Conclusion: Bmall deficiency affected the biphasic rhythm of coagulation and fibrinolysis factors predominantly in the liver. In the brain, Bmall-dependent control of t-PA gene expression was documented for the first time.