Plasminogen activator inhibitor-1 in cardiovascular cells: rapid inductionafter injecting mice with kainate or adrenergic agents

Objectives: Plasminogen activator inhibitor-1 (PAI-1) is a major anti-fibri nolytic glycoprotein thought to promote vascular diseases. Recently we have shown that systemically injecting mice with kainate, an analog of the prin cipal brain excitatory neurotransmitter glutamate, immediately induced PAI- 1 mRNA in brain vascular cells which are not known to contain glutamate rec eptors. Here we further investigated whether. (a) kainate also increases PA I-1 gene expression in the cardiac vascular bed; (b) subunits of kainate/AM PA receptors could be er;pressed in cardiac and brain vascular cells; and ( c) PAT-1 mRNA could besimilarly induced by agonists of adrenergic receptors that are candidates to act downstream in kainate-activated pathways. Metho ds: We analyzed cardiac and brain cryosections for PAT-1 mRNA, as well as m RNAs encoding three receptor subunits, by in situ hybridization using S-35- labeled specific riboprobes. PAT-1 activity was tested in cardiac homogenat es using one-phase reverse zymography. Results: Prominent PAI-1 mRNA hybrid ization signals were induced in the vascular cells of the heart, and unexpe ctedly, also in cardiocytes, within 1-2 h after injection of kainate (i.p., 11-25 mg/kg body weight); the signals persisted for at least 8 h and disap peared after 24 h. In addition, PAT-1 activity increased (similar to5 fold) 2-10 h after the treatment. In contrast, mRNAs encoding the kainate/AMPA r eceptor subunits could not be detected. The adrenergic agents adrenaline (3 .5 mg/kg) and isoproterenol (200 mg/kg) exerted kainate-like effects in car diovascular cells. Conclusions: These results revealed, for the first time, that PAI-1 gene expression can be enhanced locally in the cardiovascular s ystem by a fast-acting neurological mechanism triggered by glutamate recept ors, whose pathway and relation to catecholamines, which exerted similar ef fects, have yet to be resolved. These findings raised the possibility that excessive glutamate, or stress-related catecholamines, may increase the ris k of stroke and myocardial infarction. (C) 2001 Elsevier Science B.V. Ail r ights reserved.