JUN 07, 2021 4:28 AM PDT

Researchers Find a Way to Improve Outcomes After a Heart Attack

WRITTEN BY: Carmen Leitch

It's thought that in the United States, there is a heart attack once every 40 seconds; each year, about 80,000 Americans have a heart attack. Reperfusion therapy is often used after heart attacks to remove blockages and restore blood flow to the heart. But during that treatment, heart muscle cells often die. Researchers have now identified a molecule called protein kinase A (PKA) that's involved in the process, called heart cell necrosis. Targeting PKA for treatment might help improve outcomes after heart attacks occur. The findings have been reported in the Journal of Biological Chemistry.

Image credit: CC0 Public Domain

"Our study has found that turning off a gene that controls this protein activity increased necrotic cell death and led to more heart injury and worse heart function following heart attack in a rodent model," said study author Zhaokang Cheng, an assistant professor in the Washington State University (WSU) College of Pharmacy and Pharmaceutical Sciences. "With further research, this discovery could ultimately lead to the development of a small-molecule drug that could intervene in that pathway to limit or prevent heart muscle cell death after reperfusion therapy."

Reperfusion therapy uses mechanical force or drugs to dissolve blood clots and is a standard and effective treatment for a heart attack. It can reduce damage significantly. But it also causes damage because as blood flow rapidly rushes back into oxygen-deprived heart tissues, free radical levels increase. A surge of free radicals can trigger oxidative stress, which leads to the death of heart muscle cells and injury. This condition is known as ischemia/reperfusion injury.

From left to right, study authors Yuening Liu, Peng Xia, Zhaokang Cheng, and Jingrui Chen and graduate student Joshua Gallo. / Credit: Cori Kogan, WSU Health Sciences Spokane

It's been thought that heart cell death is basically unavoidable during the treatment, but recent work has suggested that there are ways to keep it under control. Cheng's team began to screen genes to find ones that encourage or suppress necrotic cell death. PRKAR1A caught their attention; it encodes for a protein subunit called R1alpha that helps regulate PKA activity.

When the PRKAR1A gene was deactivated in both a rodent model of necrotic cell death and cells in culture, cell death increased. Mice without the gene had worse outcomes after a heart attack compared to wild-type.

Cheng suggested that normally, a rapid increase of free radicals after the treatment will stimulate a defense mechanism in the heart that keeps free radicals in check. This research has indicated that when the R1alpha protein is removed from the heart, that so-called antioxidant defense system won't effectively respond to the free radicals, leading to oxidative stress, and subsequent cell death and heart injury.

R1alpha normally binds to PKA catalytic subunits, reducing the enzyme's activity. A lack of R1alpha leads to an increase in PKA activity, which Cheng said may prevent the antioxidant defense system from launching. If a small molecule could be designed to specifically inhibit PKA activity, it might stop necrotic cell death and improve treatment outcomes after a heart attack.

More work will be needed before that small molecule can be created and tested. The researchers are investigating whether PKA can regulate necrotic cell death in any other way.

Sources: AAAS/Eurekalert! via Washington State University, Journal of Biological Chemistry

About the Author
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Experienced research scientist and technical expert with authorships on over 30 peer-reviewed publications, traveler to over 70 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
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