September 22, 2008

Activated Protein Can Reduce Heart Damage

Illustration of a heart showing a grey damaged area

Researchers have identified a protein that, when activated, protects against injury to rat hearts. The discovery may lead to treatments for preventing heart damage during procedures such as coronary bypass surgery.

During a heart attack or certain surgical procedures, blood flow to the heart becomes restricted, depriving heart muscle of oxygen and allowing toxic metabolites to build up. This condition is called cardiac ischemia, and it can permanently injure the heart.

Scientists have recently discovered that certain compounds can reduce the amount of damage from ischemia. These include a protein called protein kinase C epsilon (PKCε), which regulates other proteins by adding a phosphate chemical group to them—a modification called phosphorylation. Because phosphorylation can help protect the heart, a team of researchers led by Dr. Daria Mochly-Rosen at Stanford University School of Medicine aimed to discover which proteins were being phosphorylated.

In work supported by NIH’s National Institute on Alcohol Abuse and Alcoholism (NIAAA) and Stanford, the researchers used a proteomic approach, correlating the phosphorylation states of proteins in the cell with heart protection. They treated ischemic rat hearts to either inhibit or activate PKCε. Then they analyzed which proteins were phosphorylated and compared that with the levels of heart damage.

In the September 12, 2008, issue of Science, the researchers reported that the status of one protein, mitochondrial aldehyde dehydrogenase 2 (ALDH2), consistently correlated with heart protection. The higher the activity of ALDH2, the smaller the heart injury. The scientists next screened for a small-molecule activator of ALDH2 and found one called Alda-1. When administered to rats before an ischemic event, Alda-1 reduced the extent of heart damage by 60%.

ALDH2 is known to remove toxic aldehydes that accumulate during cardiac ischemia, potentially explaining how ALDH2 protects the heart from damage. In laboratory experiments, the researchers found that the toxic molecules inactivated ALDH2, confirming results from other teams. Alda-1, however, blocked this inactivation, supporting the idea that ALDH2 can protect the heart by removing these toxic molecules.

This study opens the door for new approaches to treat people prone to cardiac ischemia—such as during heart surgery—by enhancing their ALDH2 activity. In laboratory experiments, the researchers found that Alda-1 was particularly effective at activating an inactive mutant form of ALDH2 that’s found in 40% of East Asian populations. A therapeutic strategy to enhance ALDH2 activity might be especially successful in patients with this mutant form.

—by Harrison Wein, Ph.D.

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