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Newly Discovered Role for Heart Response Enzyme May Yield Better Heart Failure Therapy

f PI(3)K preserves beta-adrenergic receptors on heart cells when they are chronically exposed to adrenaline and thus preserves heart function. However, it has remained unclear exactly how the heart enzyme exerts its effects on the heart receptors, Rockman added.

The researchers' experiments revealed that PI(3)K plays multiple roles as an enzyme that affect heart responses. It manufactures signaling molecules called phospholipids in the cell. And it activates other molecules, among them one called "non-muscle tropomyosin," which plays an important role in maintaining cell structure. In both cases, PI(3)K functions by attaching a phosphate group to the molecule to be activated, a process called phosphorylation.

By preventing activation of tropomyosin by PI(3)K in cells, the researchers prevented heart receptors from leaving the cell surface, thereby blocking the initial step that occurs during heart failure. Also, the researchers reported, when they eliminated tropomyosin activity altogether, they also maintained heart receptors.

"These studies demonstrate a previously unknown role for the protein phosphorylation activity of PI(3)K in receptor internalization and identify non-muscle tropomyosin as an important substrate of the enzyme's activity," Rockman said. "The findings may offer a new approach to the treatment of heart failure."

Drugs that selectively prevent PI(3)K from activating tropomyosin -- either by modifying tropomyosin or inhibiting PI(3)K's enzymatic activity -- might effectively block heart receptor loss to maintain or restore normal heart function in those at risk or suffering from heart failure, he added.

Collaborators on the study include Sathyamangla Naga Prasad, Arundathi Jayatilleke and Aasakiran Madamanchi, all of Duke. The work was supported by the National Institutes of Health.


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Source:Duke Health


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