Protein that Plays a Role in Preventing Heart Failure Could Be Good Drug Target

New research examines why some children born with heart defects also have developmental disabilities. [Image courtesy of Mark L. Riccio

A protein that helps regulate calcium signaling within heart cells could play a key role in preventing chronic heart failure, and could therefore be a good target for drug development, according to an international study led by University of Utah Health scientists. Voltage dependent anion channel 2 (VDAC2) is an outer mitochondrial membrane porin known to play a significant role in apoptosis and calcium signaling.

The researchers say disruption in the VDAC2 signaling pathway causes severe impairment of heart cell contraction, making it harder for the heart to deliver blood to the body. That finding suggests drugs and other therapeutic treatments targeting VDAC2 might help alleviate heart failure.

“Based on our human and laboratory research, it appears that If VDAC2 is not working properly, then everything in the heart can cascade downward from there,” says Stavros Drakos, Professor of Medicine, Director of Cardiovascular Research for the Division of Cardiology at University of Utah Health, and senior author of the study. “If we can figure out ways to help this protein do its job again, then it’s possible that we might be able to address heart failure far earlier in the disease process.”

The study appears today in Nature Communications.

Scientists have long known that calcium plays a vital role in the heart. Between beats, calcium levels in heart muscle cells (called myocytes) diminish, allowing the cell to relax. During contraction, a large amount of calcium surges out of a small cellular structure called the sarcoplasmic reticulum, causing the cell to contract. The constant ebb and flow of calcium in and out of the inner fluid of heart muscle cells is thus critical to keep the heart beating.

Researchers also know mitochondria rely on calcium to help produce biochemical energy. Mitochondria communicate with the sarcoplasmic reticulum, but these cellular organs’ specific role in calcium signaling and thus cardiovascular health isn’t well understood.

In their study, Drakos and colleagues sought to get a better understanding of mitochondria’s role in the calcium cycle within heart cells. VDAC2 is a protein on the outer membrane of the mitochondria that allows calcium to flow into them.  In earlier research with tissue from heart failure patients, the researchers detected a positive correlation between improved heart function and VDAC2 activity. As a result, they suspected that VDAC2 could play an important role in this disease.

In laboratory mice, they disabled, or knocked out, VDAC2. Without it, calcium flow in the mitochondria was severely impaired, and heart cells couldn’t beat properly. The mice also developed enlargement of the heart’s left ventricle or pumping chamber. This condition, called dilated cardiomyopathy, made it harder for the heart to pump blood and eventually led to heart failure and death.

Specifically, the researchers found that VDAC2 interacts with a pair of proteins in the sarcoplasmic reticulum. Hindering this protein-to-protein communication leads to impaired cellular calcium signaling and heart failure. However, restoring VDAC2 in knock-out mice reversed many of the effects of heart failure, including reduced swelling of the left ventricle, and prevented death.

In other experiments with mice that are genetically prone to develop heart failure, the researchers found that an experimental drug called efsevin, which binds to VDAC2 and increases mitochondrial calcium uptake, improved cardiovascular health. The scientists say this suggests that efsevin and other drugs that target VDAC2 are good drug candidates for further testing as treatments for heart failure.

“Our study shows the importance of VDAC2 in normal cardiac function,” says Thirupura Sundari Shankar, lead author of the study and a graduate PhD student in the Drakos lab. “Through this unique role, VDAC2 emerges as a potential therapeutic target for heart failure patients.”

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