Severance Integrative Research Institute for Cerebral & Cardiovascular Diseases (SIRIC), Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea.
Department of Neurology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea.
Int J Mol Sci. 2018 Nov 1;19(11):3428. doi: 10.3390/ijms19113428.
YAP/TAZ, a transcriptional co-activator of Hippo pathway, has emerged as a central player in vessel homeostasis such as sprouting angiogenesis and vascular barrier stabilization, during development. However, the role of YAP/TAZ in pathological angiogenesis remains unclear. Here, we demonstrated that YAP/TAZ is a critical mediator in leukocyte-endothelial adhesion induced by the vascular inflammatory cytokine TNF-α. YAP/TAZ was dephosphorylated, translocated from the cytosol to the nucleus, and activated by TNF-α in endothelial cells. A specific inhibitor of Rho GTPases suppressed the TNF-α-induced dephosphorylation of YAP. Knockdown of YAP/TAZ using siRNA significantly reduced the expression of the leukocyte adhesion molecule VCAM1 induced by TNF-α. The adhesion of monocytes to endothelial cells was also markedly reduced by YAP/TAZ silencing. However, knockdown of YAP/TAZ did not affect TNF-α-induced NF-κB signaling. Overall, these results suggest that YAP/TAZ plays critical roles in regulating TNF-α-induced endothelial cell adhesive properties without affecting the NF-κB pathway, and implicate YAP/TAZ as a potential therapeutic target for treating inflammatory vascular diseases.
YAP/TAZ，Hippo 通路的转录共激活因子，在发育过程中作为血管稳态的核心调节因子，如血管生成和血管屏障稳定中的出芽。然而，YAP/TAZ 在病理性血管生成中的作用尚不清楚。在这里，我们证明了 YAP/TAZ 是血管炎症细胞因子 TNF-α诱导的白细胞-内皮细胞黏附中的关键介质。YAP/TAZ 被去磷酸化，从细胞质转位到细胞核，并被 TNF-α激活。Rho GTPases 的特异性抑制剂抑制了 TNF-α诱导的 YAP 去磷酸化。用 siRNA 敲低 YAP/TAZ 显著降低了 TNF-α诱导的白细胞黏附分子 VCAM1 的表达。YAP/TAZ 沉默也显著降低了单核细胞与内皮细胞的黏附。然而，敲低 YAP/TAZ 并不影响 TNF-α诱导的 NF-κB 信号通路。总的来说，这些结果表明 YAP/TAZ 在调节 TNF-α诱导的内皮细胞黏附特性方面发挥着关键作用，而不影响 NF-κB 通路，并暗示 YAP/TAZ 可能是治疗炎症性血管疾病的潜在治疗靶点。
