All protein concentrations were analyzed by the method of Lowry

ascular disease. However, it remains to be established whether IL-6 fosters platelet activation, MPA formation and the development of atherosclerotic plaques or is just a surrogate marker for already existing atherosclerosis with ongoing platelet activation. Upon activation, platelets release more than 300 different bioactive proteins. To the best of our knowledge, IL-6 has not been reported to be among these platelet releasates, but there is indirect evidence that platelets have the complete machinery to produce IL-6. Further, a recent study in mice with dextran sodium sulfate -induced colonic inflammation found that the treatment of wild type mice with DSS significantly R 115777 manufacturer increased GPIIb/IIIa activation and leukocyte-platelet aggregate formation. In contrast, these platelet responses to DSS were not observed in IL-6 deficient mice. Moreover, chronic IL-6 infusion in wildtype mice reproduced the platelet abnormalities observed in DSS-colitic mice, and IL-6-infused mice also exhibited an acceleration of thrombus formation in their arterioles. In another study, the infusion of IL-6 in normal dogs resulted in an enhanced sensitivity of their platelets to activation with thrombin and platelet-activating factor. 8 / 11 IL-6 and ADMA Are Associated with Platelet Activation It has been reported that in vitro IL-6 itself does not induce platelet expression of P-selectin and their aggregation. In contrast, Oleksowicz et al. reported that the incubation of human platelets with IL-6 increased the expression of P-selectin as detected by flow cytometry as well as spheroid and dendritic platelet forms in electron microscopy. Further, they observed an increase in platelet ATP levels after both 1 min and 1 hour IL-6 platelet incubations. Finally, they demonstrated a significant reduction in dense granules in high dose IL-6 incubations by transmission electron microscopy. In a different study, the same group reported that PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19768759 platelet-rich plasma incubated with IL-6 showed a dose-dependent enhancement of agonistinducible maximal aggregation and secretion of thromboxane B2. The discrepancy between the different observations may in part be explained by the findings that activated platelets release the soluble IL-6 receptor, which, in the presence of IL-6 may induce IL-6 trans-signalling, leading to an autocrine activation loop, PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19768500 as evidenced by an increase of gp80 and gp130 content. Recently, high levels of IL-6 were associated with early and late stent thrombosis following percutaneous coronary intervention. Altogether, these findings support the role of IL-6 as mediator or even initiator of platelet activation and MPA formation. ADMA is an endogenous competitive inhibitor of nitric oxide synthase. It decreases plasma NO levels and is considered as surrogate marker for endothelial dysfunction. Previously, ADMA was shown to predict cardiovascular and all-cause mortality in patients with angiographic coronary artery disease. In the current study, ADMA was independently associated with the activation of the fibrinogen receptor GPIIb/IIIa and high ADMA levels were linked to a more pronounced expression of activated GPIIb/IIIa. These findings suggest that the interplay of the impaired endothelium with platelets, which are supposed to seal any damage, induces particularly the activation of GPIIb/IIIa, possibly to recruit further platelets from the blood stream. A higher platelet count was independently associated with a more pronounced formation of MPA. This may be