Published Online
on January 24, 2005

A more recent version of this article appeared on February 8, 2005

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Submitted on June 21, 2004
Revised on October 19, 2004
Accepted on October 27, 2004

Dipyridamole Selectively Inhibits Inflammatory Gene Expression in Platelet-Monocyte Aggregates

Andrew S. Weyrich PhD^*, Melvin M. Denis BA, Jennifer R. Kuhlmann-Eyre BA, Eliott D. Spencer PhD, Dan A. Dixon PhD, Gopal K. Marathe PhD, Tom M. McIntyre PhD, Guy A. Zimmerman MD, and Stephen M. Prescott MD

From the Departments of Internal Medicine (A.S.W., T.M.M., G.A.Z., S.M.P.) and Pathology (M.M.D., T.M.M.), Eccles Institute of Human Genetics (A.S.W., M.M.D., J.R.K.-E., E.D.S., G.K.M., T.M.M., G.A.Z.), and the Huntsman Cancer Institute (S.M.P.), University of Utah, Salt Lake City; and the Department of Biological Sciences, University of South Carolina, Columbia (D.A.D.).

^* To whom correspondence should be addressed. E-mail: andy.weyrich{at}hmbg.utah.edu.

Background--Drugs that simultaneously decrease platelet function and inflammation may improve the treatment of cardiovascular disorders. Here, we determined whether dipyridamole and aspirin, a combination therapy used to prevent recurrent stroke, regulates gene expression in platelet-monocyte inflammatory model systems.

Methods and Results--Human platelets and monocytes were pretreated with dipyridamole, aspirin, or both inhibitors. The cells were stimulated with thrombin or activated by adhesion to collagen, and gene expression was measured in the target monocytes. Thrombin-stimulated platelets increased monocyte chemotactic protein-1 (MCP-1) expression by monocytes. Dipyridamole but not aspirin attenuated nuclear translocation of NF-B and blocked the synthesis of MCP-1 at the transcriptional level. Dipyridamole delayed maximal synthesis of interleukin-8 but did not alter cyclooxygenase-2 accumulation. Adherence to collagen and platelets also increased the expression of matrix metalloproteinase-9 (MMP-9) in monocytes, a response that was inhibited by dipyridamole. In this case, however, dipyridamole did not block transcription or distribution of MMP-9 mRNA to actively translating polysomes, indicating that it regulates the expression of MMP-9 protein at a postinitiation stage of translation. Dipyridamole also blocked MCP-1 and MMP-9 generated by lipopolysaccharide-treated monocytes, indicating that at least part of its inhibitory action is unrelated to its antiplatelet properties.

Conclusions--These results indicate that dipyridamole has selective antiinflammatory properties that may contribute to its actions in the secondary prevention of stroke.

Key words: dipyridamole • gene expression • monocytes • platelets

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