Collagen Receptors as Potential Targets for Novel Anti-Platelet Agents

Abstract

Platelets have important roles in atherosclerosis and thrombosis and their inhibition reduces the risk of these disorders. There is still a need for platelet inhibitors affecting pathways that reduce thrombosis and atherosclerosis while leaving normal hemostasis relatively unaffected, thus reducing possible bleeding complications. Although combinations show progress in achieving these goals none of the present inhibitors completely fulfill these requirements. Collagen receptors offer attractive possibilities as alternative targets at early stages in platelet activation. Three major collagen receptors are assessed in this review; the alpha2beta1 integrin, responsible primarily for platelet adhesion to collagen; GPVI, the major signaling receptor for collagen; and GPIb-V-IX, which is indirectly a collagen receptor via von Willebrand factor. Several thrombosis models and experimental approaches suggest that all three are interesting targets and merit further investigation.

Identification of novel downstream targets of platelet glycoprotein VI activation by differential proteome analysis: implications for thrombus formation

“…12 Thus, platelet collagen receptors, and especially GPVI, have emerged as a highly interesting target for novel antiplatelet drugs. 13 Recent advances in mRNA and protein analysis are expected to significantly contribute to a better understanding of the fundamentals of platelet biology. Because platelets do not have a nucleus, proteomics technology is the method of choice to provide data on protein expression in these cells.…”

The Role of Platelets in Viral Hemorrhagic Fevers

“…The next most abundant receptor is GPIbα, the von Willebrand receptor, and inhibitors have been discovered and used in animal models of thrombosis [162]. Other receptors include the collagen receptors α 2 β 1 and GPVI [163], and PAR-1, the thrombin receptor [164]. As discussed above, FcRIIa is an important receptor for the interaction of DENV with platelets, and small molecule inhibitors of this receptor have been discovered [165].…”

Proteomics unravels platelet function

“…This makes the receptor as well as the associated signaling pathways attractive as therapeutic targets. 8 Indeed, one of the 9 proteins found in higher abundance upon GPVI ligation, aldose reductase, is the kind of protein one would like to "discover" with a differential proteomic approach. Functional investigations revealed that inhibition of aldose reductase impaired GPVI-induced platelet aggregation.…”

“…While initially it was believed that the reason for the different subunits in the immunoproteasome was to optimize peptide generation during antigen processing for MHC class I presentation, recent evidence suggests that additional roles exist for the immunoproteasome including cytokine production. 8 Amazingly, the use of proteasome-specific inhibitors demonstrates that the cellular processes controlled by each proteasome are in part distinct as selective inhibition of the constitutive proteasome does not affect IL-23 production in monocytes. 8 However, these selective inhibitors do not induce apoptosis when used individually, 6 thus overlapping functions are likely to exist as well.…”

“…8 Amazingly, the use of proteasome-specific inhibitors demonstrates that the cellular processes controlled by each proteasome are in part distinct as selective inhibition of the constitutive proteasome does not affect IL-23 production in monocytes. 8 However, these selective inhibitors do not induce apoptosis when used individually, 6 thus overlapping functions are likely to exist as well. Therefore, normal and transformed B cells may be dependent on both proteasomes and explain why these cells are so sensitive to proteasome inhibition.…”