Involvement of protein kinase C in HIV-1 gp120-induced apoptosis in primary endothelium

We previously showed that HIV-1 gp120-induced apoptosis in primary human um bilical Vein endothelial cell cultures (HUVEC), through CCR5 and CXCR4. Her e, we have found that agonists of protein kinase C (PKC), basic fibroblast growth factor (bFGF), and short exposure to low concentrations of phorbol e sters were found to block gp120-induced apoptosis in HUVEC cultures. PKC an tagonists, sphingosine, H7, and extended exposure of cultures to high conce ntrations of phorbol eaters were also found to block gp120-induced apoptosi s in HUVEC cultures. A significant increase in the total amount of cellular PKC enzymatic activity was observed on exposure of HUVEC to gp120. No incr ease in total PKC activity was observed on exposure of HUVECs to the natura l ligands SDF-1 alpha, or regulated-on-activation normal T-expressed and se creted (RANTES) cells, and gp120-induced PKC induction was found to be tota lly blacked by CXCR4 antibodies and partially blocked by the caspase 3 inhi bitor, DEVD-CHO. Alternatively, CXCR4 antibodies and DEVD-CHO totally block ed apoptosis. Finally, gp120-induced effects were found to be insensitive t o pertussis toxin. Accumulated evidence suggests PKC involvement at multipl e points in the gp120-induced apoptotic pathway; also suggests involvement of the CXCR4 receptor internalization pathway, and potentially suggests dif ferent downstream effects of gp120-receptor interactions and natural ligand -receptor interactions.