Activating GHRH Receptor Shown to Stimulate Cardiac Damage Repair After Myocardial Infarction
A collaborative study by several physician-scientists from the Miller School demonstrates that a growth hormone-releasing hormone agonist (GHRH-A) reverses damage to the heart and enhances recovery following a myocardial infarction. The discovery, which builds on previous research from many of the same scientists, is published in the December 26 online edition of the Proceedings of the National Academy of Sciences.
Growth hormone-releasing hormone is a key regulator of growth hormone that is produced by the brain. A previous study led by Joshua Hare, M.D., the Louis Lemberg Professor of Medicine in the Cardiovascular Division, and Andrew V. Schally, Ph.D., M.D.h.c., D.Sc.h.c., the 1977 Nobel Prize winner for Physiology or Medicine, Distinguished Medical Research Scientist of the Department of Veterans Affairs, and distinguished professor in the Department of Pathology at the Miller School, found that GHRH agonists can stimulate major recovery of the heart injured by a heart attack (PNAS, January 2010). The NIH-funded study, with Hare and Schally again collaborating, builds on that discovery, showing the importance of the GHRH signaling pathway within the heart.
“We were able to demonstrate that GHRH-A is not only effective at preventing remodeling, but can actually reverse the damage done to the chronically injured heart,” says Hare, director of the Interdisciplinary Stem Cell Institute.
Both cardiac myocytes and cardiac stem cells express the GHRH receptor, which when activated, improves injury responses to myocardial infarction. The team of scientists, which included first author Rosemeire M. Kanashiro-Takeuchi, Ph.D., research assistant professor of molecular and cellular pharmacology, and Norman L. Block, M.D., professor of pathology, urology, oncology and biomedical engineering and the L. Austin Weeks Family Professor of Urologic Research, tested the hypothesis that activation of that receptor in the heart, using a potent GHRH agonist, can reverse ventricular remodeling (heart damage) and improve cardiac function after an injury.
One month after a myocardial infarction, rats randomly received one of the following over the course of four weeks: a synthetic agonist developed in Schally’s lab, a placebo, rat recombinant GH, a highly selective GHRH antagonist (MIA-602), or a combination of the agonist and antagonist. The team used an antagonist to block the action of the agonist in order to determine whether the effects of the agonist are receptor mediated.
After measuring cardiac performance, the scientists found that GHRH-A markedly improved cardiac function and reduced the infarct size. Since there was not an increase in circulating levels of growth hormone, the scientists confirmed that the GHRH-agonist was activating the receptor mechanism of the stem cells.
“Not only did we find that the infarct size was substantially reduced,” says Kanashiro-Takeuchi, “but the amount of cardiac myocytes and nonmyocyte mitosis had noticeably increased due to GHRH-A. This indicates that growth hormone-releasing hormone agonist has a regenerative quality that can be harnessed.”
While cardiovascular disease has decreased with the development of therapeutic discoveries, it remains the No. 1 cause of death in the United States, creating a clear need for continued advances. “This finding supports the possibility that using GHRH agonists could benefit patients with acute myocardial infarction, chronic ischemic heart disease and other diseases that affect the heart muscle,” says Hare.
Improved GHRH agonists have been developed by peptide chemists Ren-Zhi Cai, Ph.D., research associate professor of pathology, and Martha Zarandi, Ph.D., D.Sc., visiting assistant professor of pathology, of Schally’s laboratory and will be available for future experimental studies and eventually clinical trials.