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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:121.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

Peripheral Circadian Clock Rhythmicity Is Retained in the Absence of Adrenergic Signaling

Dermot F. Reilly; Anne M. Curtis; Yan Cheng; Elizabeth J. Westgate; Radu D. Rudic; Georgios Paschos; Jacqueline Morris; Ming Ouyang; Steven A. Thomas; Garret A. FitzGerald

From the Institute for Translational Medicine and Therapeutics (D.F.R., A.M.C., U.C., E.J.W., R.D.R., G.P., G.A.F.) and the Department of Pharmacology (J.M., M.O., S.A.T., G.A.F.), University of Pennsylvania, Philadelphia.

Correspondence to Garret A. FitzGerald, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, 153 Johnson-Pavilion, 3620 Hamilton Walk, Philadelphia, PA 19104-6084. E-mail garret{at}spirit.gcrc.upenn.edu

Abstract

Objective— The incidence of heart attack and stroke undergo diurnal variation. Molecular clocks have been described in the heart and the vasculature; however it is largely unknown how the suprachiasmatic nucleus (SCN) entrains these peripheral oscillators.

Methods and Results— Norepinephrine and epinephrine, added to aortic smooth muscle cells (ASMCs) in vitro, altered Per1, E4bp4, and dbp expression and altered the observed oscillations in clock gene expression. However, oscillations of Per1, E4bp4, dbp, and Per2 were preserved ex vivo in the aorta, heart, and liver harvested from dopamine β-hydroxylase knockout mice (Dbh^–/–) that cannot synthesize either norepinephrine or epinephrine. Furthermore, clock gene oscillations in heart, liver, and white adipose tissue phase shifted identically in Dbh^–/– mice and in Dbh^+/– controls in response to daytime restriction of feeding. Oscillation of clock genes was similarly preserved ex vivo in tissues from Dbh^+/– and Dbh^–/– chronically treated with both propranolol and terazosin, thus excluding compensation by dopamine in Dbh^–/– mice.

Conclusions— Although adrenergic signaling can influence circadian timing in vitro, peripheral circadian rhythmicity is retained despite its ablation in vivo.

We have examined the impact of adrenergic signaling on circadian timing in vascular tissues. Using vascular smooth muscle cells and dopamine β hydroxylase knockout mice we found that adrenergic signaling can influence circadian gene expression in vitro, but peripheral circadian rhythmicity is retained despite its ablation in vivo.

Key Words: circadian • catecholamines • norepinephrine • adrenergic • sympathetic

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