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. 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-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.

Change in protein phenotype without a nucleus: translational control in platelets.

For most cells the nucleus takes center stage. Not only is it the largest organelle in eukaryotic cells, it carries most of the genome and transcription of DNA to RNA largely takes place in the nucleus. Because transcription is a major step in gene regulation, the absence of a nucleus is limiting from a biosynthetic standpoint. Consequently, the anucleate status of platelets has stereotyped it as a cell without synthetic potential. It is now clear, however, that this viewpoint is far too simplistic. In response to physiologic stimuli, platelets synthesize biologically relevant proteins that are regulated via gene expression programs at the translational level. This process does not require a nucleus; instead, it uses mRNAs and other translational factors that appear to be retained in specialized fashion as megakaryocytes generate platelets during thrombopoiesis. We highlight the molecular machinery and pathways used by platelets to translate mRNA into protein and offer insight into how these synthesized products may regulate thrombotic and inflammatory events.