Insulin-Like Hormone Helps Prevent Heart Muscle Death, Could Lead To Gene Therapies For Diabetes, Heart Disease

The findings--the first to provide a detailed picture of the link between this insulin-related hormone and heart muscle death--suggest that gene therapy might help treat a variety of heart diseases, as well as stave off heart damage that is common among diabetes patients. The study appears in the Dec. 22 issue of the Journal of Biological Chemistry.

Dr. Ping Wang, associate professor of medicine and biological chemistry, and his colleagues found that the hormone, called IGF-1 (insulin-like growth factor), kept heart muscle cells from dying by suppressing the activation of assassinator molecules that trigger cell death. The study suggests that inserting genes for the chemicals mediating IGF-1 actions could help reverse the heart muscle cell death that ultimately leads to heart failure.

"We've recently shown that circulating IGF-1 levels correlate with patient prognosis after heart attack. People with low levels of IGF-1 who had heart attacks had poorer recovery rates than heart attack victims with higher levels of the growth factor," Wang said. "This study helps us elucidate the biochemical interactions that help us further understand how IGF-1 and insulin protect heart muscle, and how we might find an effective way to enhance heart muscle survival in diabetes and in heart diseases."

The researchers found that an enzyme called PI-3 kinase mimics IGF-1's ability to inhibit the death of heart muscle cells. In cells that had genetically engineered PI-3 kinase, the activities of cell-killing molecules that trigger cell death (a process known as apoptosis) were greatly reduced, as was fragmentation of DNA from the muscle cells that occurs as cells undergo apoptosis.

The study provides more details of a biochemical pathway--consisting of IGF-1, receptors for IGF-1 on the surface of muscle cells and PI-3 kinase--that plays a major role in controlling the survival of heart muscle cells. While normal apoptosis reduces harm to the body by eliminating deteriorating cells, abnormally high rates of apoptosis can cause disease (such as the cardiac complications of diabetes) by killing more healthy cells. The scientists think that inserting genes that encourage the activation of the cell-protecting PI-3 kinase might increase heart survival after a heart attack and reduce the cardiac complications from diabetes.

"IGF-1 is structurally similar to insulin; both hormones cross-react to each others' cell surface receptors, triggering similar effects as insulin alone," Wang said. "Since we normally see increased heart muscle apoptosis in diabetes as well as other heart diseases, we think this pathway may help us develop a form of gene therapy. To do this, we first need to detail how this and other pathways regulate apoptosis in these cells."

The researchers are now working on genetically manipulating IGF-1 and signaling proteins within cells that activate it to reduce heart muscle cell death.

Wang's team was supported by grants from the National Heart, Lung and Blood Institute, the American Heart Association and the American Diabetes Association. Wang's colleagues in the study included Weihua Wu, Wen Lieng Lee, Yvonne Y. Wu, Daniel Chen, Tsun-jui Liu and Andy Jang of UCI and Prem Sharma of UC San Diego.