title: Dipyridamole selectively inhibits inflammatory gene expression in platelet-monocyte aggregates.
abstract: 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.
  
  
  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-kappaB 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.
authors.affiliation: Department of Internal Medicine, Human Molecular Biology and Genetics, Bldg 533, Room 4220, University of Utah, Salt Lake City, UT 84112, USA. andy.weyrich@hmbg.utah.edu
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Weyrich
authors.forename: Melvin M
authors.initials: MM
authors.lastname: Denis
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Kuhlmann-Eyre
authors.forename: Eliott D
authors.initials: ED
authors.lastname: Spencer
authors.forename: Dan A
authors.initials: DA
authors.lastname: Dixon
authors.forename: Gopal K
authors.initials: GK
authors.lastname: Marathe
authors.forename: Tom M
authors.initials: TM
authors.lastname: McIntyre
authors.forename: Guy A
authors.initials: GA
authors.lastname: Zimmerman
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Prescott
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D002449:Cell Aggregation; D002450:Cell Communication / Q000187:drug effects; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D004176:Dipyridamole / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D018836:Inflammation Mediators; D010975:Platelet Aggregation Inhibitors; D012333:RNA, Messenger; D004176:Dipyridamole; D020780:Matrix Metalloproteinase 9; D001241:Aspirin