Irish researchers in the US have discovered how the brain's master "clock" can control the natural 24hour rhythms in the blood vessels. The finding could improve cancer treatments or offer a solution to jet lag.
Researchers have known for years that the body's various mechanism are controlled by a circadian (24-hour) clock based in the brain, explained Prof Garret FitzGerald, chairman of the department of pharmacology at the University of Pennsylvania in Philadelphia.
The clock works to regulate essential functions. For example, it prompts the liver to begin producing essential digestive enzymes before mealtime and dampens internal bodily activity before we sleep.
Less well understood is how the master clock controls the various peripheral clocks now being discovered in a number of organs and tissues. Some answers have been provided, however, following research by Prof FitzGerald and Dr Peter McNamara, a research assistant in the Centre for Experimental Therapeutics at Pennsylvania University. The two published their findings in a recent edition of the journal, Cell.
They made two key discoveries: first, that the cardiovascular system has its own peripheral clock. They also discovered that the brain's master clock maintains control over the blood-vessel clock by the release of certain hormones and that the clock can be "reset'`, both forward and backwards.
"This is the first evidence that a hormone could control a peripheral clock," Prof FitzGerald said. "The reason this is of great interest is because there is a circadian rhythm in the incidence of heart attack and stroke."
Everyone's blood pressure rises and falls in synchronisation with the circadian clock, but rises are exaggerated in patients with high blood pressure, Prof FitzGerald explained. Blood pressure is at its highest point of the 24-hour cycle in the morning at about the time we get up, and heart attacks and strokes also occur most commonly early in the morning.
The researchers found that the peripheral clock is controlled by a combination of hormones and the activation of receptors for vitamin A. A key to the system is the release of a protein called MOP4.
The researchers studied the response of cultured human vascular smooth muscle cells in vitro and found these cells released MOP4 in a cyclical way. MOP4 has two faces and is able to connect one to BMAL1, a protein that makes the master clock work. MOP4 connects its second face to cell receptors that usually bind to vitamin A. The rise and fall of these reactions modulates the rhythm of the clock in the blood vessels.
Initially the researchers found that they could push the clock backwards. They have since found a way to push it forward using a different hormone.
The finding has important implications for medical treatments, Prof FitzGerald said. "We know that the response to certain drugs used in the treatment of cancer varies substantially depending on the time of day that they are administered," he said. "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."
Knowing which proteins are involved in this system opens up the possibility of targeting these proteins with drugs, Dr McNamara said. "If one understands exactly which component needs to be regulated to reset the biological clock, one can target just that component with drugs."