Case Western Reserve Researchers Uncover Critical Interaction in Heart Drugs

Researchers at Case Western Reserve University School of Medicine and Temple University School of Medicine have gained new insight into how classic heart drugs work—and it’s not the way they thought.

Their discovery – on the role nitric oxide (NO) plays in blocking the effect of an enzyme called GRK2 that causes heart damage – could lead to the development of better therapies to treat heart attacks and heart failure.

Specifically, the new work suggests that beta-blockers and nitroglycerin – typically administered separately – may be more effective if given to patients simultaneously.

Until now, the medical community thought that NO protected the heart by dilating blood vessels, while beta-blockers dampened GRK2’s activity.

“Everyone knew that nitric oxide, which is produced by the heart drug nitroglycerin, works to prevent heart attacks,” said Jonathan S. Stamler, MD, director, Institute for Transformative Molecular Medicine and the Robert S. and Sylvia K. Reitman Family Foundation Distinguished Chair in Cardiovascular Innovation, Case Western Reserve School of Medicine and University Hospitals (UH) Case Medical Center, and director, Harrington Discovery Institute, UH Case Medical Center. “We thought that these types of drugs worked by relaxing blood vessels and decreasing the heart’s workload – not by inhibiting the GRK2 protein.”

The study, led by Walter J. Koch, PhD, professor and chair of the Department of Pharmacology at Temple University School of Medicine, appeared in the October 29 issue of Science Signaling. It is a continuation of work that began in 2005 and included two research groups from Duke University, where Stamler was a faculty member prior to joining Case Western Reserve School of Medicine.

The Stamler laboratory previously found that an enzyme called endothelial nitric oxide synthase (eNOS), which controls the production of NO, could block the damaging effects of GRK2. His team identified the pathway NO uses to protect the heart, which is by directly blocking the enzyme.

“The beta blockers and nitroglycerin used to treat patients are not necessarily used together, nor are they the most effective inhibitors of GRK2,” Stamler said. “There are drugs in preclinical development that could be more effective in releasing NO in targeted tissue and in combating heart disease and heart failure.”

Stamler is widely recognized for his discovery of S-nitrosylation, a protein modification (a way to regulate proteins) that could impact new therapies for cardiovascular, pulmonary, musculoskeletal and neurological diseases. While the teams from Temple and Duke focused on the mechanism of the GRK2 enzyme, Stamler’s previous experience with S-nitrosylation enabled his laboratory to key in on the role and mechanism of NO in protecting heart function. There will be additional research by the four-university team, Stamler says because their emerging data suggests new targets of NO that may protect the heart. 

Founded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and is among the nation's top medical schools for research funding from the National Institutes of Health. The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching. The School's innovative and pioneering Western Reserve2 curriculum interweaves four themes--research and scholarship, clinical mastery, leadership, and civic professionalism--to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century. Nine Nobel Laureates have been affiliated with the School of Medicine.

Annually, the School of Medicine trains more than 800 MD and MD/PhD students and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News & World Report's "Guide to Graduate Education."

The School of Medicine is affiliated with University Hospitals Cleveland Medical Center, MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic, with which it established the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2002.

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Jessica Studeny