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Vitamin A calibrates a heart clock, 24-7

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10:13am, July 11, 2001
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Teenagers can make it seem as if hormones control the cycles of the heart. Now, scientists have proved it.

Researchers at the University of Pennsylvania in Philadelphia have shown that a molecular clock in the circulatory system oscillates in a 24-hour rhythm in step with cells in the brain. This heart cycle responds to a hormone derived from vitamin A.

Scientists have known for years about regions of the brain where cells cycle through a steady cadence of activity, called a circadian rhythm, that regulates sleep-wake cycles. The concentrations of molecules, called clock proteins, that drive this process also wax and wane over a 24-hour period.

Only in the past 3 years have scientists learned that the concentrations of such proteins also oscillate in organs beyond the brain, such as liver and kidneys. In the June 29 Cell, Garret A. FitzGerald, Peter McNamara, and their colleagues report that such clock proteins also cycle in the heart–and even in blood vessels. They observed these cycles in aortas removed from mice and in human blood vessel cells grown in culture.

The new data are in step with findings that blood pressure cycles over a 24-hour period, peaking in the early morning, which is when most heart attacks occur.

Since the discovery of peripheral clocks, scientists have wondered how the clocks all stay in sync. That's where vitamin A comes into the picture.

The body converts vitamin A into the hormone retinoic acid, which journeys through the bloodstream and into cells. There, it docks onto proteins called retinoic acid receptors. These receptors, in turn, enter the nucleus and affect the activity of genes. To do this, the receptors must bind to other proteins.

In what he describes as a molecular fishing expedition, McNamara found that retinoic acid receptors can bind to two clock proteins–Clock and Mop4. That suggested that retinoic acid could regulate circadian rhythms. When the team applied retinoic acid to cells, the receptor and these clock proteins stuck together more tightly.

This molecular clasp affects genes that control circadian rhythms. And it resets the clock. When the researchers applied retinoic acid to blood vessel cells in lab dishes or injected the substance into the bloodstream of mice, they found that the heart clock shifted backward by several hours. These results jibe with existing data that retinoic acid and other hormones cycle up and down through the day.

The scientists now plan to test whether retinoic acid in the circulatory system mediates the circadian rhythm originating in the brain or if the hormone modulates the peripheral rhythm directly in response to cues such as food intake.

"I would expect that in the wake of this paper, scientists will find a whole variety of hormonal signals," says Steve A. Kay of the Scripps Research Institute in La Jolla, Calif. "This is really an important piece of work." He notes that the findings may have relevance for developing new means of controlling the body's response to drugs, which can vary drastically over 24 hours.

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