Vitamin A Receptors Modulate the Wake-Sleep Cycle in Blood Vessels

Blood pressure varies in all of us throughout the day. This pattern, circadian variability, is exaggerated in patients who have high blood pressure, suggesting that the mechanisms which control this rhythm are disturbed.

Indeed, this altered biorhythm seems to have clinical consequences. Heart attacks and strokes occur most commonly early in the morning when blood pressure is at its highest point in its 24 hour cycle.

Scientists at the University of Pennsylvania School of Medicine have discovered another key to the body's circadian clock that may begin to explain these observations and lead to new treatments based on the body's timing mechanism.

Their discovery, which provides the first evidence for how hormones and vitamins can reset the human circadian clock, shows in detail how activation of vitamin A receptors can regulate the rhythm of the clock. This provides an important clue to how the master clock, which lies deep in the brain, can regulate distal organs, such as the liver, kidney and muscle by controlling clocks throughout the body.

The Penn study establishes that blood vessels contain their own peripheral circadian system, similar to clocks in other organs.

Also, significantly, it links hormonal and vitamin control for the first time to the circadian rhythms that control body temperature, sleep and wakefulness, pain sensitivity, and the response to drugs.

"We know that the responseto certain drugs used in the treatment of cancer vary substantially depending on the time of day that they are administered," said Garret

FitzGerald, MD, chairman of Penn's Department of Pharmacology and author of the study. "However, this work elucidates a molecular mechanism which permits a refinement of such chronopharmacology. Resetting the clock might have obvious application in the treatment of jet lag, but could also combine with existing knowledge to adjust circadian variability in drug response to the needs of a particular patient."

The findings will be published June 29 in the journal Cell.

"If one understands exactly which component needs to be regulated to reset the biological clock, one can target just that component with drugs" said Peter McNamara, Ph.D, who is the lead author with FitzGerald on the project. "Circadian oscillations may respond more directly to the environment. The central clock responds to changes in light

intensity whereas in a vascular clock, this signal may be blood borne hormones or metabolic signals."

McNamara was using a genetic screen to identify new proteins that interact with a retinoic acid receptor (the RXR receptor) when he found that it bound with MOP4 -- a protein very similar to one that had been previously identified as a switch for the
brain's master clock (the protein CLOCK) and the clock protein's partner, BMAL1. He showed that MOP4 protein cycled in a circadian pattern and that the retinoic acid receptors, when bound with vitamin A, modulated the rhythm of the clock in blood vessels.

"In the particular case of the cardiovascular system " added FitzGerald, " clocks probably evolved to protect the blood supply to individual organs from large shifts in blood pressure, such as might be caused by the adrenaline rush of danger or exercise. We realized 20 years ago that this system was disturbed in people with high blood pressure. This work provides the first molecular opportunity to address this problem."

Also collaborating in the research were Sang-beom Seo, PhD, of Penn's Center for Experimental Therapeutics; Radu Daniel Rudic, PhD, of Penn's Department of Pharmocology; Amita Sehgal, PhD, of the Howard Hughes Medical Institute and the Department of Neuroscience at Penn, and Debabrata Chakravarti, PhD, also of the Department of Pharmacology. The Study was funded by the National Institutes of Health.

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Editor's note:

Dr. FitzGerald may be contacted directly at: 215-898-1184.
His email is: << garret@SPIRIT.gcrc.upenn.edu >>

Dr. McNamara may be reached at 215-898-0255.
His email is << petermac@SPIRIT.gcrc.upenn.edu >>
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