FASEB: New cellular approach may change ER treatment following MI

Manipulated cell activity that occurs during the interruption of blood flow to strongly protect heart tissue in animal studies has potential to become an emergency treatment for heart attack patients, according to research published online July 7 in the Federation of American Societies for Experimental Biology.
“We decided to look for a global approach to protecting heart tissue by inhibiting enzymes that govern how cells respond to ischemia,” said study leader Peter J. Gruber, MD, PhD, a cardiothoracic surgeon at Children’s Hospital of Philadelphia and a faculty member of the University of Pennsylvania School of Medicine in Philadelphia.

The researchers used histone deactylase (HDAC) inhibitors that alter the way DNA is packaged within cells, as well as modifying the function of other proteins. Building on previous work by other researchers, who showed that HDAC inhibitors reduce ischemic injury in the brain, they used the same agents in mice with induced heart damage.

“We found significant and dramatic results in the mice,” Gruber said. “The HDAC inhibitors reduced the area of tissue injury, even when delivered an hour after the ischemic event occurred.” 

The size of the MI was reduced by more than half, according to the researchers.

In further investigating how the HDAC inhibitors acted, Gruber’s team said they found a way to block gene pathways that led to cell death and ischemia-induced vascular permeability, the leakage of fluid through blood vessels. They also said that they identified a specific molecule, HDAC4, as the likely HDAC enzyme with a critical role in affecting how cells respond to ischemia.

Gruber and colleagues reported that an important advantage of their finding is that a number of HDAC inhibitors are already used in medicine, and are well-tolerated. Although much research remains incomplete, their findings raise the possibility that existing drugs, or modified versions of them, might play an important new role in heart disease, he added.

Because the protective effect of HDAC inhibitors may occur even after the initial blockage of blood flow, therapies based on their research may lead to an emergency treatment following a heart attack, according to the researchers. In addition, because open-heart surgery for both children and adults requires a period in which the heart is stopped, such treatment might also protect tissues from the adverse effects of interrupting blood flow during surgery.

For now, Gruber said the next step for his study team will be to test how HDAC inhibitors work in protecting against ischemic injury in larger animals.

A National Institutes of Health grant partially supported the research, in addition to funding from the McCabe Foundation, the University Research Foundation and the division of pediatric cardiothoracic surgery at the Children’s Hospital of Philadelphia.