Heart Damage After Chemo Linked to Stress in Cardiac Cells

Blocking a protein in the heart that is produced under stressful conditions could be a strategy to prevent cardiac damage that results from chemotherapy, a new study suggests.

Previous research has suggested that up to a quarter of patients who receive the common chemotherapy drug doxorubicin are at risk of developing heart failure later in life. Exactly how that heart damage is done remains unclear.

In this study, scientists identified a protein called heat shock factor-1 (HSF-1) as a likely source of chemotherapy-related heart damage in mice and cell cultures. Heat shock factor-1 is known to be induced by stress - in this case, the chemotherapy treatment itself.

“We have found that a simple stress-related factor could be aggravating chemotherapy’s effect on the heart,” said Govindasamy Ilangovan, associate professor of internal medicine at Ohio State University and senior author of the study. “The results are leading us toward the idea that any additional stress could hurt the heart more than what chemotherapy itself can do.”

The researchers gave doxorubicin to two sets of mice - normal animals and mice that were genetically altered so they could not produce HSF-1. Mice without HSF-1 had healthier hearts and lived longer after the chemotherapy treatment than did normal mice.

A closer examination on the cellular level suggested that when HSF-1 is blocked in the heart, this condition allows for the activation of a gene that produces a protein to pump the chemo medicine out of heart muscle cells, preventing these cells from dying.

Ilangovan and colleagues are working to design drugs that could selectively inhibit HSF-1 in the heart as a potential additional therapy for cancer patients undergoing chemo treatment.

The research appears this week in the Proceedings of the National Academy of Sciences Online Early Edition.

Chemotherapy targets cancer cells, but it also can kill many other kinds of cells in various organs. In most cases, Ilangovan explained, organs can regenerate their cells after this damage has occurred. But cardiomyocytes, or heart muscle cells, cannot be regenerated. The loss of muscle can lead to a disorder known as dilated cardiomyopathy, which reduces the heart’s pumping action and leads to heart failure.

“This work arose from that background. We are trying to identify a factor that can be targeted to prevent the cardiomyopathy,” said Ilangovan, an investigator in Ohio State’s Davis Heart & Lung Research Institute.

Previous research had already shown that doxorubicin leads to activation of HSF-1 in the heart. The Ohio State researchers ran a number of experiments in animals and cell cultures to establish the relationship after chemo treatment between heat shock factor-1 and the gene that helps the heart, called multidrug-resistance-1 or MDR1.

In analyses using heart muscle cells from mice with and without activation of HSF-1, the researchers observed more activation of the MDR1 gene in cells lacking the HSF-1 protein compared to normal mouse heart cells. In addition, they demonstrated that the MDR1 gene prompted production of a protein on these heart cells’ surface that actually pumped doxorubicin away from the cells.