Dipyridamole selectively inhibits inflammatory gene expression in platelet-monocyte aggregates.
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.
Weyrich
Andrew S
AS
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
Denis
Melvin M
MM
Kuhlmann-Eyre
Jennifer R
JR
Spencer
Eliott D
ED
Dixon
Dan A
DA
Marathe
Gopal K
GK
McIntyre
Tom M
TM
Zimmerman
Guy A
GA
Prescott
Stephen M
SM
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
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