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Elucidating the Mechanism by Which Protamine Negates Heparin's Antiproliferative Effect on Smooth Muscle Cells
Carmen R. Berg
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Non-Scientific Abstract A cell monolayer called the endothelium lines all blood vessels. This layer secretes many substances that regulate the surrounding arterial tissues, including heparan sulfate, which prevents proliferation of smooth muscle cells which make up the next layer of the artery, the media. When the endothelium is injured, from interventions such as balloon angioplasties, the media's smooth muscle cells begin to proliferate until a new intima is formed. Protamine, which is used in some insulin preparations and to reverse blood thinning by heparin, tightly binds heparin. Because protamine can bind heparin-like molecules, it may disrupt growth regulation in arteries. Protamine has been shown to stimulate the growth of smooth muscle cells and to reverse the heparin-like molecules' regulation. This can be dangerous, as many patients administered protamine are already at risk to develop vascular disease. It is not currently understood how protamine stimulates smooth muscle cells or reverses the regulation heparin-like molecules provide to these cells. We plan to determine if protamine exerts these effects by binding heparin-like molecules, or by some other mechanism of its own. Learning more about how protamine reverses the regulatory role of heparin-like molecules will allow better understanding of the dangers involved in using protamine. Heparin-like compounds are one type of growth-inhibitory compounds secreted by an intact endothelium. Upon vascular injury that disrupts this layer, intimal hyperplasia occurs and a neointima forms. Protamine, a chelator of heparin, is used clinically to reverse systemic heparin administration and as part of common insulin preparations. Protamine's ability to reverse heparin's antiproliferative effect on arterial smooth muscle cells has led to concern regarding these clinical practices, especially because the patients are often at increased risk for vascular disease. We hope to better understand the mechanism by which protamine reverses heparin's growth-inhibitory effect on smooth muscle cells. We believe that protamine-heparin complexes change over time as they reconfigure to lower energy states, and therefore the complexes also affect cell growth in a time-dependent manner. Preliminary experimental results support this hypothesis. We plan to expand upon these studies to determine if protamine prevents heparin from being internalized in smooth muscle cells and to examine how protamine affects heparin-like compounds secreted by endothelial cells, namely heparan sulfate. The results of these studies will allow us to better understand how protamine and heparin-like compounds affect smooth muscle cells, and the possible dangers to arterial tissue associated with the clinical use of protamine. |
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