March 28, 2019
COLUMBUS, Ohio – Researchers with The Ohio State University College of Medicine, The Ohio State University Wexner Medical Center and the Davis Heart and Lung Research Institute have discovered that a certain protein expressed in the heart can help control the abnormal electrical events in cardiac cells that lead to irregular heart rhythms, or arrhythmia.
This work was recently published in the journal Circulation Research.
Research led by Mona El Refaey showed that the protein PP2A can regulate the late component of voltage-gated sodium channels. These channels are nanoscopic pores that play a critical role in cardiac muscle cell function. Normally, they open and close very quickly and in sync with other cell functions to make the heart work. In cells from sick hearts, these channels often close late, allowing for excess sodium entry and a build-up of calcium, which ultimately promotes arrhythmia.
“We know PP2A has a regulatory role in heart cells and disease, but it hasn’t been well studied and understood. This is the first time it’s been studied as a way to regulate the late component of sodium current,” said El Refaey, a postdoctoral researcher in Ohio State’s Frick Center for Heart Failure and Arrhythmia.
Previous research conducted at Ohio State identified CaM kinase II as a protein that promotes the late sodium current. However, until now, the pathways that negatively target the CaMKII/late current axis were unknown and essential for the design of new therapies.
The team observed mice modified to have increased PP2A activity and compared them with a control group. The mice were exposed to cardiac stress. The PP2A group displayed reduced cardiac muscle cell excitability in response to the increased stress. Unbiased computational analysis identified a link between PP2A complex and late sodium current.
“Electrical recording confirmed a 40 percent reduction in late component of sodium channel activity among the PP2A group and less sensitivity to stress mediated increase in late current in these mice,” said Hassan Musa, a research scientist in the Frick Center.
“This study identifies PP2A as a new molecular target for correcting the late sodium channel activity that leads to potentially fatal arrhythmia,” said Peter Mohler, vice dean for research and senior author of the study.
Cardiac arrhythmias are common and increase with age. Arrhythmias cause more than 250 thousand deaths annually in the U.S. alone. Some arrhythmias are brief and harmless, such as a flutter or a few skipped beats. Other forms can last longer and affect how the heart works, or cause a heart attack or sudden cardiac arrest.
Recent clinical trials have shown potential for treating arrhythmia with drugs that block late current. However, the drugs can also affect other sodium current functions.
“While further testing is needed, this work shows PP2A holds promise as a targeted molecular therapy with more selective and more potent effects for those who develop heart arrhythmias,” said Dr. K. Craig Kent, dean of the College of Medicine.
Funding from the National Institutes of Health and the Ohio State J.B. Project helped support this research.
Media Contact: Marti Leitch, 614-293-3737 or Marti.Leitch@osumc.edu