Yan S F, Lu J, Zou Y S, Kisiel W, Mackman N, Leitges M, Steinberg S, Pinsky D, Stern D
Department of Surgery, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
J Biol Chem. 2000 Apr 21;275(16):11921-8. doi: 10.1074/jbc.275.16.11921.
Fibrin deposition is a salient feature of hypoxemic vasculature and results from induction of tissue factor. Such tissue factor expression in an oxygen deficient environment is driven by the transcription factor Early Growth Response (Egr)-1. Using homozygous null mice for the protein kinase C beta-isoform gene (PKCbeta null), PKCbeta is shown to be upstream of Egr-1 in this oxygen deprivation-mediated pathway for triggering procoagulant events. Whereas wild-type mice exposed to hypoxia (6%) displayed a robust increase in tissue factor transcripts and antigen, and vascular fibrin deposition, PKCbeta null animals showed a markedly blunted response. Consistent with a central role for Egr-1 in hypoxia-induced expression of tissue factor, PKCbeta null mice subjected to oxygen deprivation displayed at most a minor elevation in Egr-1 transcripts, antigen, and intensity of the gel shift band by electrophoretic mobility shift assay, compared with normoxic animals. These data firmly establish PKCbeta as a trigger for events leading to induction of Egr-1 and tissue factor under hypoxic conditions, and provide insight into a biologic cascade whereby oxygen deprivation recruits targets of PKCbeta and Egr-1, thereby amplifying the cellular response.
纤维蛋白沉积是低氧血管系统的一个显著特征，由组织因子的诱导产生。在缺氧环境中，这种组织因子的表达由转录因子早期生长反应（Egr）-1驱动。利用蛋白激酶Cβ亚型基因纯合缺失小鼠（PKCβ缺失），研究表明在这种缺氧介导的触发促凝血事件的途径中，PKCβ位于Egr-1的上游。野生型小鼠暴露于低氧环境（6%）时，组织因子转录本和抗原以及血管纤维蛋白沉积显著增加，而PKCβ缺失动物的反应明显减弱。与Egr-1在缺氧诱导组织因子表达中起核心作用一致，与常氧动物相比，缺氧的PKCβ缺失小鼠通过电泳迁移率变动分析检测到的Egr-1转录本、抗原以及凝胶迁移带强度最多只有轻微升高。这些数据明确证实PKCβ是缺氧条件下导致Egr-1和组织因子诱导事件的触发因素，并深入揭示了一种生物学级联反应，即缺氧招募PKCβ和Egr-1的靶点，从而放大细胞反应。
