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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1768-1775.)
© 1999 American Heart Association, Inc.

Thrombosis

Endothelin-1 Enhances Plasminogen Activator Inhibitor-1 Production by Human Brain Endothelial Cells via Protein Kinase C-Dependent Pathway

Raphael Zidovetzki; Jin-Lin Wang; Jeong A. Kim; Peijia Chen; Mark Fisher; Florence M. Hofman

From the Departments of Biology and Neuroscience (R.Z.), University of California, Riverside; and Departments of Pathology (J.-L.W., P.C., F.M.H.) and Neurology (J.A.K., M.F.), University of Southern California School of Medicine, Los Angeles.

Correspondence to Florence M. Hofman, PhD, USC School of Medicine, HMR 312, 2011 Zonal Ave, Los Angeles, CA 90033.

Abstract—The effects of endothelin-1 (ET-1) on the production of plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (t-PA) by human brain-derived endothelial cells in culture were studied. At 100 nmol/L, ET-1 increased PAI-1 production by 88±6% within 72 hours, and increased PAI-1 mRNA expression within 1 hour of stimulation; there was no significant effect on t-PA production. PAI-1 activity was also examined and found to increase with ET-1 treatment. Suboptimal concentrations of ET-1 and tumor necrosis factor- (TNF-) acted synergistically to increase PAI-1 production. ET-1 activated protein kinase C and cAMP-dependent protein kinase pathways within 3 to 5 minutes of treatment, with the peak at 10 minutes. Activation of protein kinase C by phorbol-12-myristate-13-acetate (PMA) resulted in increased PAI-1 production, whereas activation of the cAMP-dependent protein kinase by forskolin or dibutyryl cAMP (dBu-cAMP) significantly decreased PAI-1 production. However, simultaneous activation of protein kinase C by PMA and cAMP-dependent protein kinase by dBu-cAMP only slightly attenuated PMA-induced PAI-1 increase. Inhibition of protein kinase C by GF-109213X abolished the effects of ET-1. These results demonstrate that ET-1 and TNF- function synergistically to induce procoagulant activity of brain endothelial cells in a process that involves a protein kinase C-dependent pathway.

Key Words: endothelin • plasminogen activator inhibitor 1 • brain • endothelium • protein kinase C • cAMP

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