GRK5's role in restenosis

Nov 28 2005

Researchers at Jefferson Medical College have begun to clarify the role of a protein - and potential drug target - in the process by which arteries re-clog after treatment.

The process - called restenosis - is due to an unregulated growth and movement of cells in the vessel.

Scientists have known that G-protein coupled receptors are involved in the growth and migration of cells, and alterations in the signaling through these receptors are involved in cardiovascular disease. The protein GRK5, part of the family of G-protein coupled receptor kinases, shuts down this signaling. GRK5 is present in vascular smooth muscle cells, which line the inside of blood vessels, and its levels rise in heart failure and high blood pressure.

Andrea Eckhart, Ph.D., associate professor of medicine in the Center for Translational Medicine in the Department of Medicine at Jefferson Medical College and of Thomas Jefferson University in Philadelphia and her co-workers, wanted to see what if any role GRK5 had in restenosis. In one experiment, they found evidence that GRK5 was present in the smooth muscle cells in mice with a damaged left carotid artery, an experimental condition that fosters the process of cell buildup and restenosis. The researchers thought that by overexpressing GRK5, they could desensitize certain G-protein coupled receptors, stopping restenosis. They found this to be true in the laboratory test tube: high levels of GRK5 could block excessive cell growth. But when they injured the left carotid artery in mice with a foreign gene that made extra GRK5 only in the vascular smooth muscle, cell proliferation continued.

They turned to gene therapy and an adenovirus, which enabled them to express GRK5 in any cell. When they injured the left carotid artery in mice, they found cell growth in the artery was dramatically reduced, even four weeks after the injury compared to control mice treated with a different virus.

"This gives us insight that it's probably not only the vascular smooth muscle cells that are contributing to the formation of restenosis," says Dr. Eckhart. "It's probably something else."

The group is planning to look at other potentially contributing cell types next. "If we knew it was epithelial cells or bone marrow derived stem cells, for example, we could target those cells with more specific drugs," she notes.