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Posted 08.12.05

MU Researchers Identify Key Factor in Onset of Heart Disease

COLUMBIA, MO -- Each year about 950,000 Americans die of cardiovascular disease, according to the Centers for Disease Control, making it the leading cause of death in the United States. One symptom of heart disease is a thickening of artery walls, a condition known as atherosclerosis. New research conducted at the University of Missouri-Columbia has identified one of the causes of this condition and could lead to an effective treatment.

Cheikh Seye, MU assistant research professor in biochemistry, and a team of researchers from the "Inflammation Research Group," led by professor Gary Weisman at MU's Life Sciences Center, found that a particular nucleotide receptor, P2Y2, plays a significant role in abnormal cell growth that leads to atherosclerosis. Nucleotide receptors act as receiving antennae on a cell's surface. When a nucleotide comes into contact with the receptor, it flips a switch that makes a cell perform a certain function. In this case, the nucleotides adenosine 5'-triphosphate (ATP) and uridine 5-triphosphate (UTP) encounter the receptor on endothelial cells that line the interior of arteries, and smooth muscle cells that make up the blood vessel wall. In turn, the receptor causes smooth muscle cells to multiply and blood monocytes, a type of white blood cell, to bind to endothelial cells.

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"Our earlier research found that ATP and UTP bind to the P2Y2 receptor, which induces an internal thickening of the artery," Seye said. "Not only do nucleotides increase the amount of thickening, but they also increase the number of monocytes that pass through the endothelium into the muscle cells of the artery, causing inflammation. We wanted to learn what causes these cells to pass through the endothelium."

They found that when endothelial cells are injured or stressed, something that happens naturally, or in medical procedures used to clear clogged arteries such as balloon angioplasty, they trigger a chemical reaction that allows monocytes in the blood to stick to the endothelial wall. Once the monocytes are attached to the endothelial wall, they penetrate to the smooth muscle cells of the artery, causing inflammation. This inflammation stimulates the release of ATP and UTP, which bind to the P2Y2 receptors causing new cell growth that thickens the artery.

Now that they've demonstrated that the P2Y2 receptor is a vital element in the initial onset of cardiovascular disease, Seye and his team are working to regulate the receptor to prevent the development of cardiovascular disease.

"We've designed molecules that will selectively block production of the P2Y2 receptor," Seye said. "We¿re hoping that if that protein is blocked, we can retard the disease."

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The press release was based on a series of publications (see citations below) with several others in the publication in preparation. 

Seye, C.I., Kong, Q., Erb, L., Garrad, R.C., Krugh, B.W., Wang, M., Turner, J.T., Sturek, M., Gonzalez, F.A., and Weisman, G.A. (2002) Functional P2Y2 Nucleotide Receptors Mediate Uridine 5’-Triphosphate-Induced Intimal Hyperplasia in Collared Rabbit Carotid Arteries. Circulation 106, 2720-2726.

Seye, C.I., Yu, N., Jain, R., Kong, Q., Minor, T., Newton, J., Erb, L., Gonzalez, F.A., and Weisman, G.A. (2003) The P2Y2 Nucleotide Receptor Mediates UTP-induced Vascular Cell Adhesion Molecule-1 Expression in Coronary Artery Endothelial Cells. J. Biol. Chem. 278, 24960-24965.

Seye, C.I., Yu, N., González, F.A., Erb, L., and Weisman, G.A. (2004) The P2Y2 Nucleotide Receptor Mediates Vascular Cell Adhesion Molecule-1 Expression through Interaction with VEGF Receptor-2 (KDR/Flk-1). J. Biol. Chem. 279, 35679-35686.

Liu, J., Liao, Z., Camden, J., Griffin, K.D., Garrad, R.C., Santiago-Perez, L.I., Gonzalez, F.A., Seye, C.I., Weisman, G.A., and Erb, L. (2004) Src homology 3 Binding Sites in the P2Y2 Nucleotide Receptor Interact with Src and Regulate Activities of Src, Proline-rich Tyrosine Kinase 2, and Growth Factor Receptors. J. Biol. Chem. 279, 8212-8218.

Shen, J., Seye, C.I., Wang, M., Weisman, G.A., Wilden, P.A., and Sturek, M. (2004) Cloning, Upregulation, and Mitogenic Role of the Porcine P2Y2 Receptor in Coronary Artery Smooth Muscle Cells.  Mol. Pharm.  66, 1265-1274.

Kaczmarek, E., Erb, L., Koziak, K., Jarzyna, R., Wink, M.R., Guckelberger, O., Blusztajn, K.B., Trinkaus-Randall, V., Weisman, G.A., and Robson, S.C. (2005) Modulation of Endothelial Cell Migration by Extracellular Nucleotides.  Involvement of Focal Adhesion Kinase and Phosphatidylinositol 3-Kinase-mediated Pathways.  Thromb. Haemost. 93, 735-742.


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