This transient rise in PC concentration in circulation, that was achieved twice a week in our model, was apparently not enough to initiate protective signaling that lasted long enough to provide long term protection against atherosclerosis development during the time span of our study. We have however observed a clear effect of hS360A-PC and hwt-APC administration on IL-6 levels in plasma. The decrease in concentration of the pro-inflammatory cytokine IL-6 after hS360A-PC and hwt-APC treatment can possibly be explained by inhibited IL-6 release by neutrophils as a result of hPC treatment. Conflicting reports on the role of IL-6 in the development of murine atherosclerosis have appeared; some studies show that IL-6 promotes atherosclerosis while other studies show that IL-62/2 mice are more atherogenic than control mice, so it is not clear what the exact contribution of IL-6 to atherogenesis is. In hS360A-PC treated mice we found an increased level of MCP-1. Remarkably, this was not accompanied by increased percentages of leukocytes and macrophages in plaques and therefore EX 527 likely had no effects on plaque development. In hS360A-APC treated mice the phenotype of the atherosclerotic plaques was slightly changed. Plaques contained significantly less collagen, while the infiltration of both leukocytes and T-cells was increased. Both an increase in activated immune cells and a decrease of collagen in plaques are associated with a more unstable plaque phenotype. Analysis of other cardiovascular studies which have studied the in vivo effects of PC in a cardiovascular context reveals that administration of APC has mainly been studied in models of acute diseases like I/R injury and stroke. In most of these experimental models administration of APC improved primary and secondary outcome variables, like survival, lesion/ edema volume, cardiac/neurological function and lowered the concentration of inflammation markers. For comparison between experiments it is important to realize that administration of 0.2 mg/kg APC i.v. and 0.8 mg/kg APC i.p. result in similar APC plasma pharmacokinetic profiles. Wang et al. show that an APC mutant that is not able to cleave PAR-1 does not have any protective effect, while an APC mutant with greatly impaired anticoagulant function was as effective as wt-APC in decreasing lesion volume and improving neurological function. This result in itself suggests that mainly the cytoprotective PAR-1-dependent effects of APC, rather than the anticoagulant functions of APC, are important for protection in cardiovascular disease. However, the current study showed that hS360A-APC was as effective as hwt-APC in decreasing lesion volume in myocardial I/R injury, although this variant had strongly decreased anti-coagulant activity and was not able to cleave PAR-1. We hypothesize that hS360A-APC was protective because it can bind through its Gla-domain to EPCR and thereby promotes protective PAR-1 signaling via endogenous mAPC and thrombin. Both these serine proteases are known to be formed during I/R damage.