A healthy heart needs two proteins working together

According to National Institutes of Health scientists and their collaborators, two proteins that bind to stress hormones work together to maintain heart health in mice. These proteins, the hormone receptors known as glucocorticoid receptors (GR) and mineralocorticoid receptors (MRs), work together to promote heart health. When the signaling between the two receptors is unbalanced, the mice have heart disease.

The work, published on April 16 in Scientific signage, can lead to the development of therapeutic compounds that help people at increased risk of heart attack.

Stress increases the risk of dying from heart failure by inducing the adrenal glands to make a hormone called cortisol. Cortisol is involved in combat or flight response and binds to RBCs and MRs in various body tissues to reduce inflammation, among other functions. If the level of cortisol remains too high over a long period, common risk factors for heart disease may occur, such as an increase in cholesterol and glucose in the blood and high blood pressure.

Lead author Robert Oakley, Ph.D., first identified a dysfunction of genetic resources in the 1990s while a graduate student and was working with John Cidlowski, Ph.D. North Carolina to Chapel Hill. Shortly after the discovery, other scientists determined that the risk of heart disease was higher in people with higher than average amounts of these modified genetic resources. Based on this discovery, Oakley and Cidlowski tested a strain of heartless GR mice in their laboratory at the National Institute of Environmental Health Sciences (NIEHS), which is part of the NIH. These animals spontaneously developed enlarged hearts leading to heart failure and death. When the team produced a mouse strain lacking mouse MRI, the animals heart functioned normally.

Oakley and Cidlowski then wondered what would happen if both receptors were absent from the heart tissue. So they created another strain of mice without GR and MR. They guessed that these double knockout mice would have the same heart problems or more serious heart problems as mice without GR.

"To our surprise, hearts were resistant to heart disease," Oakley said.

Cidlowski theorized why double knockout mice seemed to be protected against heart disease. He added that these mice did not exhibit the genetic changes leading to heart failure, as in mice lacking genetic resources, while simultaneously exhibiting a gain in function of the genes that protect the heart. Although the hearts of these mice function normally, they are slightly enlarged compared to cores without MR.

The ultimate goal, however, is to treat people with heart disease. Cidlowski said that in the past, when researchers designed synthetic hormones for this task, they made molecules that only work on a single receptor.

"We suggest that since GR and MR cooperate, a better approach is to make a drug that works on both receptors simultaneously," said Cidlowski. "It could help heart patients and prevent other heart diseases."