Cheng Gang, Zhang Hua, Yang Xianglei, Tzima Eleni, Ewalt Karla L, Schimmel Paul, Faber James E
Dept. of Cell and Molecular Physiology, 6309 MBRB, Univ. of North Carolina, Chapel Hill, NC 27599-7545, USA.
Am J Physiol Regul Integr Comp Physiol. 2008 Oct;295(4):R1138-46. doi: 10.1152/ajpregu.90519.2008. Epub 2008 Aug 27.
Mini-tyrosyl-tRNA synthetase (mini-TyrRS), the N-terminal domain of tyrosyl-tRNA synthetase, is a recently identified protein released by endothelial cells that exhibits angiogenic and leukocyte chemoattractant, ELR-motif (Glu-Leu-Arg)-dependent activities in vitro. We sought to determine whether exogenous mini-TyrRS exerts these and other cytokine-like actions in physiological and pathological settings in vivo. High-dose mini-TyrRS (600 microg.kg(-1).day(-1)) augmented while low-dose mini-TyrRS (3 microg.kg(-1).day(-1)), unexpectedly, inhibited angiogenesis in the ischemic mouse ear. Enhanced angiogenesis was associated with increased CD45- and CD4-positive leukocyte accumulation. Mini-TyrRS also had biphasic actions on both basal and mustard oil-evoked and VEGF-evoked leakage of Evan's blue dye-albumin in nonischemic ear and in endothelial cell monolayers, that is, low-dose inhibited and high-dose augmented leakage. Mutation of the ELR motif of mini-TyrRS abolished the above activities. Mini-TyrRS was reduced (immunoblot) in extracts of ischemic calf muscle and in thoracic aorta explants exposed to hypoxia or VEGF. Inhibition of VEGF with a soluble Flt1 "trap" protein abolished this hypoxic-induced reduction in mini-TyrRS in aorta explants. These data show that mini-TyrRS has dose-dependent biphasic effects on ischemic angiogenesis and vascular permeability in vivo, that is, antiangiogenic and antipermeability activities at low concentration and proangiogenic, propermeability activities at high concentrations.
小酪氨酸-tRNA合成酶（mini-TyrRS）是酪氨酸-tRNA合成酶的N端结构域，是内皮细胞最近鉴定出的一种蛋白质，在体外具有血管生成和白细胞趋化活性，且依赖于ELR基序（Glu-Leu-Arg）。我们试图确定外源性mini-TyrRS在体内生理和病理环境中是否发挥这些以及其他类似细胞因子的作用。高剂量的mini-TyrRS（600μg·kg⁻¹·天⁻¹）可促进血管生成，而低剂量的mini-TyrRS（3μg·kg⁻¹·天⁻¹）却意外地抑制了缺血小鼠耳部的血管生成。血管生成增强与CD45阳性和CD4阳性白细胞积聚增加有关。Mini-TyrRS对非缺血耳部和内皮细胞单层中伊文思蓝染料-白蛋白的基础渗漏、芥子油诱发的渗漏以及VEGF诱发的渗漏也有双相作用，即低剂量抑制渗漏，高剂量增强渗漏。Mini-TyrRS的ELR基序突变消除了上述活性。在缺血小腿肌肉提取物以及暴露于缺氧或VEGF的胸主动脉外植体中，mini-TyrRS减少（免疫印迹法）。用可溶性Flt1“陷阱”蛋白抑制VEGF可消除主动脉外植体中这种缺氧诱导的mini-TyrRS减少。这些数据表明，mini-TyrRS在体内对缺血性血管生成和血管通透性具有剂量依赖性双相作用，即低浓度时具有抗血管生成和抗通透性活性，高浓度时具有促血管生成和促通透性活性。
