Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Geriatrics & Gerontology, Bmal1, Aging, Diurnal rhythm, Coagulation, Fibrinolysis, Haemostasis, BLOOD-BRAIN-BARRIER, T-PA, MYOCARDIAL-INFARCTION, CIRCADIAN VARIATION, FIBRINOLYTIC FACTORS, CEREBRAL EDEMA, ONSET, ACTIVATION, FLUCTUATIONS, FREQUENCY, ARNTL Transcription Factors, Animals, Blood Cell Count, Blood-Brain Barrier, Body Composition, Brain, Circadian Rhythm, Hemostasis, Male, Mice, Mice, Inbred C57BL, Myocardium, Plasminogen Activator Inhibitor 1, Tissue Plasminogen Activator, 11 Medical and Health Sciences, Gerontology, 32 Biomedical and clinical sciences, 42 Health sciences

Abstract:

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. Bmal1 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, FVII, protein S and anti-thrombin 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: Bmal1 deficiency affected the biphasic rhythm of coagulation and fibrinolysis factors predominantly in the liver. In the brain, Bmal1-dependent control of t-PA gene expression was documented for the first time.