Deficiency in core circadian protein Bmal1 is associated with a prothrombotic and vascular phenotype.
Aging is associated with both the disturbances of circadian rhythms and a prothrombotic phenotype. It remains poorly understood how the circadian system regulates thrombosis, a critical outcome of aging-related cardiovascular disease. Using multiple in vivo models, we now show that mice with genetic ablation of the core clock gene Bmal1, which display pre-mature aging, have a dramatic prothrombotic phenotype. This phenotype is mechanistically linked to changes in the regulation of key risk factors for cardiovascular disease. These include circulating vWF, fibrinogen, and PAI-1, all of which are significantly elevated in Bmal1(-/-) mice. We also show that major circadian transcriptional regulators CLOCK and Bmal1 directly regulate the activity of vWF promoter and that lack of Bmal1 results in upregulation of vWF both at mRNA and protein level. Here we report a direct regulation of vWF expression in endothelial cells by biological clock gene Bmal1. This study establishes a mechanistic connection between Bmal1 and cardiovascular phenotype.
Somanath
Payaningal R
PR
Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, HM 1200 Medical College of Georgia, Augusta, Georgia 30912, USA. sshenoy@mail.mcg.edu
Podrez
Eugene A
EA
Chen
Juhua
J
Ma
Yi
Y
Marchant
Kandice
K
Antoch
Marina
M
Byzova
Tatiana V
TV
D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001683:Biological Clocks; D002460:Cell Line; D005340:Fibrinogen / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D010974:Platelet Aggregation / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D058258:Serpin E2 / Q000235:genetics / Q000378:metabolism; D013927:Thrombosis / Q000209:etiology / Q000378:metabolism*; D013997:Time Factors; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism
D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D012333:RNA, Messenger; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D014841:von Willebrand Factor; D005340:Fibrinogen