Involvement of circadian clock gene Clock in diabetes‐induced circadian augmentation of plasminogen activator inhibitor‐1 (PAI‐1) expression in the mouse heart

Abstract

Diabetes is associated with an excess risk of cardiac events, and one of the risk factors for infarction is the elevated-levels of plasminogen activator inhibitor-1 (PAI-1). To evaluate how the molecular clock mechanism is involved in the diabetes-induced circadian augmentation of PAI-1 gene expression, we examined the expression profiles of PAI-1 mRNA in the hearts of Clock mutant mice with streptozotocin-induced diabetes. Circadian expression of PAI-1 mRNA was blunted to low levels under both normal and diabetic conditions in Clock mutant mice, although the expression rhythm was augmented in diabetic wild-type (WT) mice. Furthermore, plasma PAI-1 levels became significantly higher in WT mice than in Clock mutant mice after STZ administration. Our results suggested that the circadian clock component, CLOCK, is involved in the diabetes-induced circadian augmentation of PAI-1 expression in the mouse heart.

Identification of the circadian clock‐regulated E‐box element in the mouse plasminogen activator inhibitor‐1 gene

“…These classical E-boxes are also involved in hypoxia-induced PAI-1 gene expression [15]. Recently, we showed that CLOCK-regulated transactivation of the PAI-1 gene plays an important role in diabetes-and obesity-induced hypofibrinolysis in mice [10,16]. Further elucidation of the regulation mechanisms of PAI-1 gene expression by circadian clock molecules should reveal the underlying mechanisms of not only circadian hemostatic changes but also various pathophysiologic conditions in vivo.…”

Genetic Components of the Circadian Clock Regulate Thrombogenesis In Vivo

“…Previous studies have shown an impact of CLOCK [31][32][33] and CRY 34 on the circadian oscillation of plasma PAI-1 and its mRNA. 15,35,36 Plasma levels of PAI-1 and tPA were measured to determine whether fluctuations in fibrinolytic activity related to the diurnal variation in the thrombotic response to injury.…”

CLOCK deubiquitylation by USP8 inhibits CLK/CYC transcription in Drosophila

“…In contrast, UBP8, a component of the yeast SAGA complex, deubiquitylates H2B and stimulates transcription by enhancing Lys4 trimethylation of H3. Also notable is mammalian usp2; its mRNA cycles, and its transcription is under CLOCK/BMAL1 control (Oishi et al 2003(Oishi et al , 2005. USP2 was shown more recently to stabilize BMAL1 and CRY1 by deubiquitylation in mouse livers (Scoma et al 2011;Tong et al 2012).…”