Journal
PLOS ONE
Volume 7, Issue 7, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0041054
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Funding
- National Institutes of Health [R01 AT004837]
- American Heart Association [0855583G]
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Aims: ICAM-1-dependent leukocyte recruitment in vivo is inhibited by the vitamin E isoform d-alpha-tocopherol and elevated by d-gamma-tocopherol. ICAM-1 is reported to activate endothelial cell signals including protein kinase C (PKC), but the PKC isoform and the mechanism for ICAM-1 activation of PKC are not known. It is also not known whether ICAM-1 signaling in endothelial cells is regulated by tocopherol isoforms. We hypothesized that d-alpha-tocopherol and d-gamma-tocopherol differentially regulate ICAM-1 activation of endothelial cell PKC. Results: ICAM-1 crosslinking activated the PKC isoform PKC alpha but not PKC beta in TNF alpha-pretreated human microvascular endothelial cells. ICAM-1 activation of PKC alpha was blocked by the PLC inhibitor U73122, ERK1/2 inhibitor PD98059, and xanthine oxidase inhibitor allopurinol. ERK1/2 activation was blocked by inhibition of XO and PLC but not by inhibition of PKC alpha, indicating that ERK1/2 is downstream of XO and upstream of PKC alpha during ICAM-1 signaling. During ICAM-1 activation of PKC alpha, the XO-generated ROS did not oxidize PKC alpha. Interestingly, d-alpha-tocopherol inhibited ICAM-1 activation of PKC alpha but not the upstream signal ERK1/2. The d-alpha-tocopherol inhibition of PKC alpha was ablated by the addition of d-gamma-tocopherol. Conclusions: Crosslinking ICAM-1 stimulated XO/ROS which activated ERK1/2 that then activated PKC alpha. ICAM-1 activation of PKC alpha was inhibited by d-alpha-tocopherol and this inhibition was ablated by the addition of d-gamma-tocopherol. These tocopherols regulated ICAM-1 activation of PKC alpha without altering the upstream signal ERK1/2. Thus, we identified a mechanism for ICAM-1 activation of PKC and determined that d-alpha-tocopherol and d-gamma-tocopherol have opposing regulatory functions for ICAM-1-activated PKC alpha in endothelial cells.
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