Shear flow attenuates serum-induced STAT3 activation in endothelial cells.

Vascular endothelial cells (ECs) are constantly exposed to flow-induced shear stress. Shear stress is known to induce signaling cascades, including the extracellular signal-regulated protein kinase (ERK) pathway. transcription factor plays a key role in cytokine stimulation. Recent studies indicate that duanyu18133 is involved in growth factor-induced cell cycle. In the present study, we have examined duanyu18133 activation of ECs under conditions of shear flow. Bovine aortic ECs cultured with serum at static state show a serum concentration-dependent phosphorylation at Tyr-705 of whereas there is a constant basal phosphorylation at Ser-727. In ECs subjected to shear flow, a shear dose-dependent phosphorylation of Ser-727 and ERK1/2 was observed. In contrast, a concomitantly shear dose-dependent inhibition of phosphorylation at Tyr-705 was exhibited. Shear stress on ECs increased the association of ERK1/2 to ECs treated with MEK inhibitor (U0126 or PD98059) consistently and significantly reduced the shear-induced ERK1/2 and Ser-727 phosphorylation, indicating that ERK1/2 is upstream of Ser-727 phosphorylation. Interestingly, shear-induced inhibition in Tyr-705 phosphorylation was abolished in these same inhibitor-treated ECs. Similarly, ECs transfected with a dominant positive mutant of MEK1 enhanced the phosphorylation of Ser-727 with the attenuation of the Tyr-705 phosphorylation. In contrast, when ECs were transfected with dominant positive mutant of MEKK1, JNK upstream, no change in the phosphorylation of Ser-727 and Tyr-705 was observed. These results indicate that shear flow induces the phosphorylation of Ser-727 via ERK1/2 pathway, and this Ser-727 phosphorylation inhibits Tyr-705 phosphorylation in duanyu18133. As a result, shear flow reduced the translocation of duanyu18133 into nucleus. This study shows for the first time that shear flow may play a significant role by attenuating duanyu18133 activation and thus may reduce inflammatory responses and/or serum-induced endothelial proliferation.

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