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EDITORIAL FOCUS
and RhoA cross talk
1Department of Pharmacology, Rush University Medical Center, Chicago; 2Department of Medicine, University of Illinois, Chicago; 3Department of Medicine, John H. Stroger Hospital of Cook County, Chicago, Illinois; and 4Research Service, Stratton Veterans Affairs Medical Center, Albany, New York
Submitted 4 January 2005 ; accepted in final form 4 March 2005
Lysophosphatidylcholine (LPC) is a bioactive proinflammatory lipid that can be generated by pathological activities. We investigated the hypothesis that LPC signals increase in endothelial permeability. Stimulation of human dermal microvascular endothelial cells and bovine pulmonary microvascular endothelial cells with LPC (10–50 µM) induced decreases (within minutes) in transendothelial electrical resistance and increase of endothelial permeability. LPC activated (within 5 min) membrane-associated PKC phosphotransferase activity in the absence of translocation. Affinity-binding analysis indicated that LPC induced increases (also by 5 min) of GTP-bound RhoA, but not Rac1 or Cdc42. By 60 min, both signaling pathways decreased toward baseline. Inhibition of RhoA with C3 transferase inhibited 
50% of LPC-induced resistance decrease. Pretreatment with PKC inhibitor Gö-6983 (concentrations selective for classic PKC), PMA-induced depletion of PKC
, and transfection of antisense PKC oligonucleotide each prevented 40–50% of the LPC-induced resistance decrease. Furthermore, these three PKC inhibition strategies inhibited 60–80% of the LPC-induced GTP-bound RhoA. These results show that LPC directly impairs the endothelial barrier function that was dependent, at least in part, on cross talk of PKC and RhoA signals. The evidence indicates that elevated LPC levels can contribute to the activation of a proinflammatory endothelial phenotype.
protein kinase C; signal transduction
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