Protein found to set the heart’s cadence

The heart’s got rhythm, thanks to molecular timekeepers.

Researchers at the University of Utah in Salt Lake City have discovered a new role for a well-known metabolic protein — as a conductor setting the pace of the heart’s daily cadence and the rise and fall of blood pressure. The finding, reported in the Dec. 3 Cell Metabolism, links the heart’s daily clock with other metabolic functions of the body, helping to explain why sleep disturbances may lead to high blood pressure and diabetes.

Heart rate and blood pressure rise and fall over the course of the day in a regular pattern, one of the body’s best-known circadian rhythms. Blood pressure falls at night, rises sharply just before a person wakes up and then peaks about midmorning. The steep rise in blood pressure may be the reason people are more likely to have heart attacks and strokes in the morning than at other times of day.

Most of the body’s daily patterns are controlled by a master clock in the brain, but each cell in the body contains timekeeping proteins as well. Scientists knew that heart rate and blood pressure are governed by a daily clock, but didn’t know whether the heart and blood vessels keep their own time or dance to the beat of the body’s master clock.

Tianxin Yang, a physiologist at the University of Utah, and his colleagues stumbled upon the answer to that question while investigating the cardiovascular side benefits of some widely used diabetes drugs, such as rosiglitazone. The drugs not only help treat type 2 diabetes, but also improve cardiovascular health.

The team sought to understand the protein these drugs target: Peroxisome proliferator-activated receptor-gamma, or PPARgamma, is involved in controlling how the body uses glucose and lipids. To learn more about the protein’s role in the vascular system, the researchers genetically engineered mice to lack the protein only in the heart and blood vessels.

The team found that mice lacking PPARgamma only in the heart and blood vessels don’t have dramatic differences in blood pressure over the course of the day the way normal mice do. That result means that PPARgamma must be involved in setting the clock that governs heart and blood pressure rhythms, the team reports. The researchers demonstrated that PPARgamma and the diabetes drugs probably set the clock by stimulating production of another protein, BMAL1, which is a major gear in all the body’s molecular clocks.

The possibility that the main brain-clock helps set the pace of the heart and blood vessels cannot be ruled out, but the finding is evidence that the vascular system has its own clock, one that is tied to other metabolic processes, says Yang. “This peripheral clock is definitely required to maintain the normal cardiovascular rhythm,” he says.

Because PPARgamma is affected by metabolism and diabetes drugs, it is likely a clock that can be wound by outside factors. “This is a nice paper that clarifies one mechanism by which environmental influences can impinge on the molecular clock,” says Garret FitzGerald, a pharmacologist at the University of Pennsylvania School of Medicine in Philadelphia.

Other metabolic factors are also likely to influence the body’s rhythms, says FitzGerald.

“The more we learn about the clock from mutant mice, the more important it appears to be in the regulation of cardiovascular and metabolic function,” he says.