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New Pathway to Treat Heart Failure

Researchers discover a new way to keep the heart pumping, which could lead to new drugs.

New Pathway to Treat Heart Failure

About 5.7 million Americans have heart failure, and half of them will die from the disease within five years, according to the Centers for Disease Control and Prevention. Two processes help drive the disease: a weakened heart muscle and the death of heart cells. Beta-blockers, commonly used to treat heart disease, work by blocking beta-adrenergic receptors in the heart, saving heart cells from cell death. But beta-adrenergic receptors also help keep the heart pumping—a function this medication also blocks.

Jefferson researchers have discovered how to bypass this problem by tapping an alternate pathway that both blocks damage to the heart and helps it keep pumping. The research, published online in the Proceedings of the National Academy of Sciences USA, offers the possibility of developing a new class of heart failure medications.

“There’s much more work to be done, but this is an excellent example of how a little curiosity in the basic research laboratory can lead to discoveries that have the potential to change the way we treat a very common and deadly illness,” says senior author Jeffrey Benovic, PhD, Thomas Eakins Professor and Chair of the Department of Biochemistry and Molecular Biology.

Beta1-adrenergic receptors are primarily responsible for the heart’s contraction and are targeted by traditional beta-blockers. Benovic’s lab, however, developed a series of molecules called pepducins that were derived from pieces of the beta2-adrenergic receptor and that they found could selectively activate the very receptor they came from.

It was while former graduate student Richard Carr, in Benovic’s lab, was characterizing the properties of these pepducins that he noticed the molecule shared similar characteristics to a common heart failure medication called carvedilol. They sent the pepducin to their colleague Douglas Tilley, PhD, at Temple University, who tested how heart cells responded.

When Tilley pulsed heart cells with the pepducin, the cells started to beat more forcefully. The pepducin used was specific for the beta2-adrenergic receptor pathway and didn’t have any effect on the beta1 receptors. The researchers had demonstrated for the first time that contraction of heart muscle cells could be triggered via the beta2-adrenergic receptor, using this novel pepducin.

Through further analysis, the researchers showed that the pepducin activated the ability of the beta2-adrenergic receptor to interact with a secondary signaling molecule called beta-arrestin and that it was this interaction that promoted the heart cells to beat. In addition, the pepducin only activated the beta2 receptor to 40 or 50 percent. By tinkering with the pepducin molecules, says Benovic, “we think we can get full activation.”

The next steps are to design a better version of the pepducin. In addition, Benovic and colleagues plan to screen existing small molecules to see if one can mimic the action of the pepducin. They also plan to study the structure of the pepducin and the beta2 receptors to gain better insight into the design of more effective pepducin-like molecules.