Cardiovascular diseases account for more deaths than any other disease in western countries. In addition, treatment of individuals with vascular diseases is expected to account for more than $300 billion in health care spending in 2010. Evidence suggests that the drug heparin can be an effective short-term treatment for many of the symptoms of cardiovascular disease, and laboratory studies indicate that heparin slows vascular smooth muscle cell growth, a component of late stage vascular disease. The long-term research goals in the PI's laboratory are to understand how heparin treatment results in changes in vascular cell function. Such knowledge is likely to contribute to the development of advanced treatments for vascular diseases. Previously, the PI's laboratory developed antibodies that mimic heparin effects on vascular cells in culture and those antibodies have been used in studies that resulted in evidence for how vascular smooth muscle cell proliferation is inhibited.
The research aims for the current proposal will enhance that understanding by first evaluating the entire response to heparin rather than only those specific changes that were predicted in advance. This will involve using array technology that can examine changes in many different genes at one time. Specific targets identified using this technology will be evaluated further. Second, the protein and gene for the heparin receptor will be identified using mass spectrometry techniques developed for protein identification and sequence determination. Sequence information from the identified protein will be used to create new tools that will be used to further confirm the identification of the heparin receptor. Third, based on previous work from our laboratory that identified a likely signal system from the heparin receptor, we propose to compare the results of signaling through the heparin receptor and receptors that trigger similar intracellular pathways to increase our understanding of heparin signaling. Fourth, cardiovascular disease has a significant inflammatory component that is likely to also be a target of heparin action, consistent with our preliminary results. The ability of heparin treatment to decrease inflammatory responses in vascular smooth muscle cells will be evaluated. In addition, changes in expression of specific genes induced by inflammatory mediators that cover a range of significantly altered gene types will be examined in cultured endothelial cells with and without concurrent heparin treatment. If heparin treatment results in decreased inflammatory changes in gene expression, the data will support the hypothesis that heparin signaling acts counter to inflammatory signaling in the vasculature. Coupled with the other results of this work, these data will provide a solid understanding of the mechanisms by which heparin alters vascular cell behavior and suggestions for ways in which the heparin receptor could be a target for advanced therapies for vascular diseases.
Deaths from cardiovascular disease and spending on treatments for individuals suffering from these diseases are major factors in the costs of health care. The drug heparin has been suggested as a treatment that could decrease progression of the disease, but we have a limited understanding of how heparin might work to help slow disease progress. The proposed research is designed to increase our understanding of how the drug heparin works at the molecular level to decrease inflammation in blood vessels, and should therefore facilitate development of new treatment strategies for vascular disease.
