Circadian expression of plasminogen activator inhibitor-1 in angiotensin II type 1a receptor knockout mice

Both the peripheral biological clock and the renin-angiotensin system regulate mRNA expression of plasminogen activator inhibitor-1 (PAI-1). Our objective was to determine whether angiotensin II (Ang II) type 1 (AT1) receptor-mediated signaling contributes to the development of circadian expression of PAI-1 and clock genes in the heart, aorta, liver, and kidney. We sacrificed AT1a receptor knockout (AT1a-KO) and wild-type (WT) 12 week-old mice every 4 hr. We examined mRNA expression for PAI-1 and clock genes (Per2, Bmal1, and Clock) in heart, aorta, liver, and kidney by using the quantitative reverse transcription-polymerase chain reaction. PAI-1 mRNA showed circadian oscillation with a peak occurring during the light phase in the heart, liver, aorta, and kidney of WT mice. Peak expression of PAI-1 in the liver and aorta was decreased in AT1a-KO mice. On the other hand, cardiac PAI-1 expression in AT1a-KO mice was reduced in the dark phase, during which time its expression level was low. There were no significant differences between WT and AT1a-KO mice in renal PAI-1 expression. Clock genes oscillated synchronously in WT and AT1a-KO mice, and there were no significant differences between the WT and the AT1a-KO mice in their expression. Plasma angiotensin II showed little oscillation in the WT mice. We conclude that AT1a receptor-mediated Ang II signaling modulates the circadian expression of PAI-1 in an organ-specific manner. The effect of the renin-angiotensin system on PAI-1 expression appears to be independent of peripheral clock gene expression.