This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 111/5/633    most recent 01.CIR.0000154607.90506.45v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Weyrich, A. S. Articles by Prescott, S. M. Search for Related Content PubMed PubMed Citation Articles by Weyrich, A. S. Articles by Prescott, S. M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ACETYLSALICYLIC ACID Medline Plus Health Information Blood Thinners Related Collections Secondary prevention Gene expression Gene regulation Other Stroke Treatment - Medical Platelets

(Circulation. 2005;111:633-642.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

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; 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.).

Correspondence to Andrew S. Weyrich, PhD, Human Molecular Biology and Genetics, Bldg 533, Room 4220, University of Utah, Salt Lake City, UT 84112. E-mail andy.weyrich{at}hmbg.utah.edu

Received June 21, 2004; revision received October 19, 2004; accepted October 27, 2004.

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

This article has been cited by other articles:

				M. C. Mulero, A. Aubareda, M. Orzaez, J. Messeguer, E. Serrano-Candelas, S. Martinez-Hoyer, A. Messeguer, E. Perez-Paya, and M. Perez-Riba Inhibiting the Calcineurin-NFAT (Nuclear Factor of Activated T Cells) Signaling Pathway with a Regulator of Calcineurin-derived Peptide without Affecting General Calcineurin Phosphatase Activity J. Biol. Chem., April 3, 2009; 284(14): 9394 - 9401. [Abstract] [Full Text] [PDF]

				P. N. Shashkin, G. T. Brown, A. Ghosh, G. K. Marathe, and T. M. McIntyre Lipopolysaccharide Is a Direct Agonist for Platelet RNA Splicing J. Immunol., September 1, 2008; 181(5): 3495 - 3502. [Abstract] [Full Text] [PDF]

				C. Patrono, C. Baigent, J. Hirsh, and G. Roth Antiplatelet Drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 199S - 233S. [Abstract] [Full Text] [PDF]

				G. A. Zimmerman and A. S. Weyrich Signal-Dependent Protein Synthesis by Activated Platelets: New Pathways to Altered Phenotype and Function Arterioscler Thromb Vasc Biol, March 1, 2008; 28(3): s17 - s24. [Abstract] [Full Text] [PDF]

				H.-H. Kim and J. K. Liao Translational Therapeutics of Dipyridamole Arterioscler Thromb Vasc Biol, March 1, 2008; 28(3): s39 - s42. [Abstract] [Full Text] [PDF]

				S. R. Steinhubl, J. J. Badimon, D. L. Bhatt, J.-M. Herbert, and T. F. Luscher Clinical evidence for anti-inflammatory effects of antiplatelet therapy in patients with atherothrombotic disease Vascular Medicine, May 1, 2007; 12(2): 113 - 122. [Abstract] [PDF]

				S. Eligini, S. S. Barbieri, I. Arenaz, E. Tremoli, and S. Colli Paracrine up-regulation of monocyte cyclooxygenase-2 by platelets: Role of transforming growth factor-{beta}1 Cardiovasc Res, May 1, 2007; 74(2): 270 - 278. [Abstract] [Full Text] [PDF]

				A. Gamboa, R. Abraham, A. Diedrich, C. Shibao, S. Y. Paranjape, G. Farley, and I. Biaggioni Role of Adenosine and Nitric Oxide on the Mechanisms of Action of Dipyridamole Stroke, October 1, 2005; 36(10): 2170 - 2175. [Abstract] [Full Text] [PDF]