Stress hormone receptors known as the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) were found to act in concert to help support heart health, stated scientists at the National Institutes of Health and their collaborators. When the signaling between the two receptors is out of balance, the mice have heart disease. When the signaling between the two receptors is out of balance, the mice have heart disease.
The work, published April 16 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.
Oakley and Cidlowski 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," Oakley said.
Cidlowski theorized why the double-knockout mice appeared to be protected against heart disease. He 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.
The end goal, however, is treating people with heart disease. Cidlowski 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," Cidlowski said. "It could help patients with heart disease and prevent subsequent heart diseases."