The Effects of Aspirin, Celecoxib, and Laminar Shear Stress on TNFα-iInduced EMP Formation
Grimm, Heather A.
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We used an in vitro cell model to investigate the effect of aspirin, celecoxib, laminar shear stress (LSS), or the combination of aspirin and LSS, and the combination of celecoxib and LSS in preventing TNF-a induced EMPs in HUVECs. We assessed the effect of various pre-established inflammatory and atherothrombotic treatments and combination of treatments on TNF-a induced EMPs from both activated and apoptotic endothelial cells. In doing so, we also investigated changes seen in COX-1, COX-2, and their respective enzymes thromboxane and prostacyclin. We found that in the presence of an inflammatory challenge in the form of TNF-α, which caused a significant disruption of EC function, aspirin and celecoxib actually proved to be augmenting TNF-α-induced increases in EMP formation indicative of EC apoptosis, likely independent of the COX pathway. Further, neither compound affected TNF-α-induced increases in EMP formation indicative of EC activation. This unfavorable response was compounded by either compounds inability to affect TNF-α-induced decreases in eNOS expression, questioning the effect of either aspirin or celecoxib on endothelial function. The potentially unfavorable effect of either compound on EC function was ameliorated when aspirin and celecoxib were combined with LSS, as evidenced by a similarly positive effect of LSS and LSS combination pre-treatment on TNF-α-induced changes in CD31 EMP accumulation and eNOS expression. Overall, exercise-mimetic levels of LSS proved to be the most effective means in improving EC homeostasis and preventing significant disruption of EC function by TNF-α. The beneficial effect of LSS pre-treatment on TNF-α-induced accumulation of EMPs suggestive of cellular activation being partially mediated by COX-1, while improvement in eNOS is independent of COX. In conclusion, aspirin and celecoxib might be ineffective in improving endothelial function and preventing early signs of atherosclerotic development when the endothelium is presented with an inflammatory challenge. While either compound have demonstrated clinical efficacy in some cases in the prevention and treatment of cardiovascular disease, the effect might be mediated through the respective compounds’ effect on platelets more so than ECs.
Subjectlaminar shear stress