Protein kinase C-beta and oxygen deprivation - A novel Egr-1-dependent pathway for fibrin deposition in hypoxemic vasculature

Fibrin deposition is a salient feature of hypoxemic vasculature and results from induction of tissue factor. Such tissue factor expression in an oxyge n 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 (PKC beta null), PKC beta 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 increas e in tissue factor transcripts and antigen, and vascular fibrin deposition, PKC beta null animals showed a markedly blunted response. Consistent with a central role for Egr-1 in hypoxia-induced expression of tissue factor, PK C beta null mice subjected to oxygen deprivation displayed at most a minor elevation in Egr-1 transcripts, antigen, and intensity of the gel shift ban d by electrophoretic mobility shift assay, compared with normoxic animals. These data firmly establish PKC beta as a trigger for events leading to ind uction of Egr-1 and tissue factor under hypoxic conditions, and provide ins ight into a biologic cascade whereby oxygen deprivation recruits targets of PKC beta and Egr-1, thereby amplifying the cellular response.