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Temple researchers uncover clues to how existing heart drugs work
Date:11/5/2013

oduced in GRK2 to prevent NO from binding (a process called nitrosylation). The mutation rendered the mice resistant to nitrosylation by eNOS and dramatically increased the extent of heart injury. In addition, drugs that normally donate NO to help protect the heart were ineffective in the mice, indicating that NO binding to GRK2 is central to the ability of NO donor drugs to protect the heart from ischemic injury.

The therapeutic implications of the findings are far-reaching. They suggest, for example, that NO donor drugs, which carry and then release NO in targeted tissues, could be important in the treatment of heart failure. Currently, however, few NO donor drugs are available for clinical use. The results also indicate that existing heart failure therapies, including beta-blockers and nitrates, which have long been thought to benefit the heart primarily through vasodilation (widening of blood vessels, a process controlled by NO), might exert their most significant effects in part by blocking GRK2 activitya previously unknown mechanism.

According to Jonathan S. Stamler, MD, a collaborator on the study and Professor of Medicine and Director of the Institute for Transformative Molecular Medicine at Case Western Reserve University, "Neither [beta-blockers nor nitrates] in their current form are ideal." Better would be agents that are capable of increasing NO bioavailability or inhibiting GRK2 directly.

"GRK2 inhibitors may have very real therapeutic benefits, especially in the context of heart failure and ischemic heart disease," Stamler said. βARKct, which Koch's laboratory has been developing as a tool for gene therapy, is one such example.

The research marks another important contribution in cardiovascular research by scientists at Temple's Center for Translational Medicine. "Novel therapeutics for heart disease are needed," Koch said "We plan to continue to look for compounds that can inhibit GRK2."


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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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