Vitamin A Receptors Modulate the Wake-Sleep Cycle in
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
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,"
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
"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.
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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