Understanding of cell protection mechanism points to therapies to prevent heart attacks and strokes

Queen's study finds genes cooperate to protect aortic smooth muscle cells

Kingston, Ont. An understanding of how two genes cooperate to protect aortic muscle cells points to new therapies to treat arteriosclerosis, the major cause of heart attack and stroke, a study by Queen's University researchers concludes.

The study, released July 14 by the American Heart Association, found that a gene called heme oxygenase-1 (HO-1) markedly protects the arteriosclerois-prone human aortic smooth muscle cells from death after exposure to high concentrations of reactive oxygen species (ROS). ROS are a natural by-product of the body's metabolism of oxygen and are known by scientists for their signaling role in cellular activity.

The findings revealed that HO-1 exerted these remarkable protective effects by cooperating with another protective gene, Akt. The protective effect of HO-1 was dependent on the activation of Akt and vice-versa, indicating that these two protective genes work co-dependently to exert their beneficial effects.

"It appears that these two genes act as dance partners in the complex tango of cellular protection, with neither one wanting to assume the lead role," says the study's lead author Luis G. Melo, Associate Professor of Physiology and Canada Research Chair in Molecular Cardiology at Queen's.

He says the findings point to a new therapy for preventing clogging in the arteries to avoid heart attacks and strokes.

Smooth muscle cells make up the wall of blood vessels and are the prime target for development of the plaque that causes arteries to harden. The smooth muscle cells provide stability to the plaque, thereby preventing it from rupturing and causing clogging of the blood vessels (thrombosis). The major cause of plaque rupture is the loss of smooth muscle cells due to cell death caused by an excess hydrogen peroxide.

In the study, funded by CIHR and the Heart and Stroke Foundation of Ontario, investigators used a harmless virus to express the HO-1 protein in the cells. The cells were then exposed to high levels of hydrogen peroxide and their survival was monitored over 48 hours. Cells over-expressing HO-1 were seen to have a remarkable ability to escape apoptosis, a form of cell suicide, even after being exposed to toxic levels of hydrogen peroxide.

"A strategy aimed at protecting smooth muscle from undergoing apoptosis is a logical therapeutic target for plaque stabilization. One such approach may heed our findings and use gene therapy to deliver the HO-1 gene to the atherosclerotic plaques," says Dr. Melo.

"Our laboratory is actively pursuing the development and preclinical testing of these new gene therapies using sophisticated viral vector systems, which are highly responsive to the pathological conditions of the plaque itself. Although the possibility of using these experimental therapies in the clinical setting is years away, we believe that we are in the right path, and one worth pursuing, considering the devastating socio economic effects of this disease."

Protection of Human Vascular Smooth Muscle Cells From H202-Induced Apoptosis Through Functional Codependence Between HO-1 and AKT will appear in the September issue of Arteriosclerosis, Thrombosis and Vascular Biology, the official journal of the Council in Arteriosclerosis, Thrombosis and Vascular Biology of the American Heart Association.

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The study was conducted by graduate student Keith R. Brunt. Other members of the team are Keith Fenrich, Gholam Kiani and Chris Ward, all of Queen's Department of Physiology, and Yat Tse and Stephen Pang of Anatomy and Cell Biology.

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A pdf version of the study is available upon request.

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