Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 289, Issue 2, Pages L176-L185Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00003.2005
Keywords
protein kinase C; signal transduction
Categories
Funding
- NHLBI NIH HHS [HL-69585, HL-71081, HL-52597, HL-59901] Funding Source: Medline
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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 mu M) 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 similar to 50% of LPC-induced resistance decrease. Pretreatment with PKC inhibitor Go-6983 ( concentrations selective for classic PKC), PMA-induced depletion of PKC alpha, and transfection of antisense PKC alpha 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 alpha and RhoA signals. The evidence indicates that elevated LPC levels can contribute to the activation of a proinflammatory endothelial phenotype.
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