Calcium channel involved in coronary artery relaxation

November 20, 2003

A genetically engineered mouse initially designed to explore muscle repair mechanisms instead helped University of Iowa scientists understand how a certain type of calcium channel helps coronary arteries to relax.

The study, reported in the Nov. 21 issue of Science, sheds light on the role of T-type calcium channels in coronary artery relaxation and may provide insight into causes of some types of coronary artery disease.

Calcium channels are proteins that allow calcium ions to flow into cells. This influx of calcium plays a role in many important cell functions including muscle contraction.

Previous research suggesting that T-type calcium channels may be involved in cellular events critical for muscle regeneration made this protein an interesting target for the UI team led by Kevin Campbell, Ph.D., professor and interim head of physiology and biophysics, professor of neurology in the UI Roy J. and Lucille A. Carver College of Medicine, and a Howard Hughes Medical Institute (HHMI) investigator.

However, when the researchers genetically engineered mice to lack the T-type calcium channel, the mice did not have skeletal muscle defects. Instead, the mice developed cardiomyopathy, or damaged heart muscle.

"Loss of the protein caused heart disease in the mice," Campbell said. "But T-type calcium channels are not expressed in normal adult heart muscle cells, they are expressed in the smooth muscle that surrounds the heart's blood vessels. This suggested that the problem might lie in the smooth muscle tissue."

Chien-Chang Chen, Ph.D., UI postdoctoral fellow in Campbell's lab and first author of the study, took a closer look at the coronary arteries in mice without the calcium channel. He and his colleagues found that the coronary arteries were abnormally constricted and misshapen.

Chen and Kathryn Lamping, Ph.D., UI associate professor of internal medicine and pharmacology and a member of the Iowa Cardiovascular Center, tested how loss of the calcium channel affected blood vessel contraction. Losing this channel did not seem to impair blood vessel contraction. This result is somewhat surprising because calcium influx through calcium channels is known to cause muscle contraction.

However, when the researchers treated blood vessels from the genetically altered mice with a vasodilator (a substance that causes blood vessels to relax) the vessels did not relax as much as they should. Specifically, relaxation mediated through a substance called nitric oxide was impaired. The UI team found that other relaxation pathways were not impaired by loss of this calcium channel.

"You might expect that losing a calcium channel would make it easier for the vessel to relax," Chen said. "But we found that the vessels actually don't relax as well as the normal vessels."

To prove that the T-type calcium channel was essential for normal nitric oxide-controlled relaxation, the UI researchers blocked the channel in normal mice. They found that this treatment resulted in constricted coronary arteries that resembled the abnormal coronary arteries seen in the mice that lacked the channel.

Abnormal or restricted blood flow to heart muscle can lead to heart damage because cells that are deprived of oxygen and nutrients die. In the heart, the dead muscle cells cannot usually be replaced with healthy, new muscle cells and connective tissue fills the space. This process, known as fibrosis, results in muscle loss, weakening the heart muscle and altering its electrical properties, which keep the heart pumping in rhythm.

"The function of this channel is clearly very important for blood flow to the heart via the coronary artery," Campbell said.

The team then explored how the absence of this calcium channel caused the relaxation defect.

Another type of channel protein that plays a role in regulating relaxation of blood vessels is the calcium-activated potassium channel. When these channels open, potassium ions exit the cell, triggering an inhibition of contraction.

"We propose that the calcium influx from the T-type channel triggers the potassium channel to open and that is how this calcium channel is involved in relaxation. Without it, the smooth muscle is not able to relax properly," Chen said. "Loss of the calcium channel decreases the activity of the potassium channel and that decreases the relaxation ability of the smooth muscle."

To test that idea, the UI team used a chemical to open the potassium channel artificially. In the genetically engineered mice, this procedure allowed the coronary vessels to relax.

The UI study shows that the T-type calcium channel is involved in coronary artery relaxation and the findings suggest that this protein may be a potential therapeutic target for some types of coronary artery disease. However, the researchers still do not understand all the details of how the calcium channel functions and further research is needed to fully understand this channel's role in coronary artery relaxation and other cellular processes.

In addition to Campbell, Chen and Lamping, who also is a researcher at the Iowa City Veterans Affairs Medical Center (VAMC), other UI researchers on the team included Daniel Nuno; Rita Barresi, Ph.D., postdoctoral fellow; Sally Prouty; Julie Lavoie, Ph.D., postdoctoral researcher; Sarah England, Ph.D., associate professor of physiology and biophysics; Curt Sigmund, Ph.D., professor of internal medicine and physiology and biophysics; Robert Weiss, M.D., associate professor of internal medicine and staff physician at the VAMC; and Roger Williamson, M.D., professor of obstetrics and gynecology. Leanne Cribbs, Ph.D., assistant professor of medicine and physiology at Loyola University Medical Center, Maywood, Ill.; and Joseph Hill, M.D., Ph.D., chief of cardiology at the University of Texas, Southwestern Medical Center, Dallas, were also part of the research team.
-end-
The study was funded in part by grants from the National Institutes of Health, the American Heart Association and the Muscular Dystrophy Association.

University of Iowa Health Care describes the partnership between the UI Roy J. and Lucille A. Carver College of Medicine and UI Hospitals and Clinics and the patient care, medical education and research programs and services they provide. Visit UI Health Care online at http://www.uihealthcare.com.

STORY SOURCE: University of Iowa Health Science Relations, 5135 Westlawn, Iowa City, Iowa 52242-1178

University of Iowa

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