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Clues to heart disease in unexpected places, Temple researchers discover
Date:4/12/2013

in ischemic heart cells the movement of GRK2 from the cell membrane to mitochondria is chaperoned by a substance called heat-shock protein 90 (Hsp90), which is produced in cells in response to stress. By blocking Hsp90's ability to bind to GRK2, the researchers were able to prevent the enzyme's delivery to mitochondria.

They reached the same result after mutating a residue called Ser670 in the tail end of GRK2's amino acid structure. When the Ser670 residue is activated by a chemical signal, Hsp90 is nudged into action, attaching to GRK2 and carrying it to mitochondria. Mutation of Ser670 also resulted in a wholesale reduction in pro-death signaling in affected heart cells. The effects were observed in human heart muscle cells grown in the laboratory and in mice that had experienced induced heart attacks. The results are detailed in the April 12 issue of the journal Circulation Research.

Koch explained that the translation of the new findings to the clinic, where they would benefit patients, lies in developing new therapeutic approaches that are capable of limiting both the activity of GRK2 and its ability to associate with mitochondria.

"We have a great opportunity here to develop new medicines against heart failure and improve upon this significant disease syndrome," he said. He added that this will take some time but that molecular and pharmacological strategies against GRK2 are in the works. "We are developing a gene therapy tool known as the ARKct, which is a peptide inhibitor of GRK2, and are quite excited about a clinical trial."

Koch and his team have shown in pre-clinical studies that delivery of the ARKct to failing hearts can inhibit GRK2 and thereby protect the heart from death. In the new study, ARKct was found to block the enzyme's transit to mitochondria after ischemia, an important step now believed to contribute to the peptide's beneficial effects in heart failure.

There is much yet to learn about GRK
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Contact: Jeremy Walter
Jeremy.Walter@tuhs.temple.edu
215-707-7882
Temple University Health System
Source:Eurekalert

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