Submitted February 5, 2009
Accepted June 18, 2009
A non-fibrin macromolecular cofactor for tPA-mediated plasmin generation following cellular injury
Andre L. Samson, Rachael J. Borg, Be'eri Niego, Connie H.Y. Wong, Peter J. Crack, Tang Yongqing, and Robert L. Medcalf*
Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia
Department of Pharmacology, University of Melbourne, Melbourne, Victoria, Australia
* Corresponding author; email: robert.medcalf{at}med.monash.edu.au.
Tissue-type plasminogen activator (tPA) is an extracellular protease that converts plasminogen into plasmin. For tPA to generate plasmin under biological conditions, a cofactor must first bring tPA and plasminogen into physical proximity. Fibrin provides this cofactor for tPA-mediated plasmin generation in blood. Despite being naturally devoid of fibrin(ogen), tPA-mediated plasmin formation also occurs in the brain. The fibrin-like cofactor(s) that facilitates plasmin formation in the injured brain has remained unknown. Here we show that protein aggregates formed during neuronal injury provide a macromolecular, non-fibrin cofactor that promotes tPA-mediated plasmin formation and subsequent cell breakdown. The binding of plasminogen and tPA to these protein aggregates occurs via distinct mechanisms. Importantly, non-neuronal cell types also exhibit this cofactor effect upon injury indicating a general phenomenon. This novel cofactor identified in non-viable cells has ramifications for ischemic stroke where tPA is used clinically and where plasmin activity within the injured brain is unwanted. A means of selectively inhibiting the binding of tPA to non-viable cells while preserving its association with fibrin may be of benefit for the treatment of ischemic stroke.
