Healthy hearts need two proteins working together

Two proteins that bind to stress hormones work together to maintain a healthy heart in mice, according to the scientists. These proteins, stress hormone receptors known as the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), act in concert to help support heart health. When the signaling between the two receptors is out of balance, the mice have heart disease.

The work, published in Science Signaling, may lead to the development of therapeutic compounds that help people with an increased risk of a heart attack.

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

Lead author first identified a malfunctioning GR in the 1990s. Soon after the discovery, other scientists determined that people with above average amounts of this altered GR had greater risk of heart disease. Based on this finding, the researchers tested a mouse strain without heart GR in their lab. These animals spontaneously developed enlarged hearts leading to heart failure and death. When the team produced a mouse strain missing cardiac MR, the animals' hearts functioned normally.

The authors then wondered what would happen if both receptors were missing from heart tissue, so they made another mouse strain that lacked GR and MR. They guessed that these double-knockout mice would have the same or worse heart problems as the mice without GR. "To our surprise the hearts were resistant to heart disease," the author said.

They theorized why the double-knockout mice appeared to be protected against heart disease. They said these mice did not have the gene changes that lead to heart failure as seen in mice lacking GR, while simultaneously exhibiting a gain in function of genes that protect the heart. Although the hearts of these mice function normally, they are slightly enlarged compared to the hearts with no MR. Gene expression analysis revealed the loss of gene changes associated with impaired Ca2+ handling, increased oxidative stress, and enhanced cell death and the presence of gene changes that limited the hypertrophic response and promoted cardiomyocyte survival in the double knockout hearts. Re-expression of MR in cardioGRMRdKO hearts reversed many of the cardioprotective gene changes and resulted in cardiac failure.

The end goal, however, is treating people with heart disease. The author said, in the past, when researchers designed synthetic hormones for this task, they made molecules that only worked on one receptor.

"We propose that since GR and MR cooperate, a better approach is to make a drug that works on both receptors simultaneously," the author said. "It could help patients with heart disease and prevent subsequent heart diseases."

https://www.niehs.nih.gov/news/newsroom/releases/2019/april16/index.cfm