The role of apoptosis in LDL transport through endothelial cell monolayers

We have previously shown that leaky junctions associated with dying or dividing cells are the dominant pathway for LDL transport under convective conditions, accounting for more than 90% of the transport. To explore the role of apoptosis in the leaky junction pathway, TNF¿ and cycloheximide (TNF¿/CHX) were used to induce an elevated rate of apoptosis in cultured bovine aortic endothelial cell (BAEC) monolayers and the flux of LDL was measured. Treatment with TNF¿/CHX induced a 14.8-fold increase in apoptosis and a 4.4-fold increase in LDL permeability. These increases were attenuated by treatment with the caspase inhibitor Z-VAD-FMK. Relative to TNF¿/CHX treatment, apoptosis was reduced by 3.1-fold and permeability was reduced by 2-fold when the monolayers were treated with both TNF¿/CHX and 100 ¿M Z-VAD-FMK. In addition, we tested the effect of simvastatin on the apoptosis and permeability of TNF¿/CHX treated monolayers. Apoptosis was reduced by 2-fold and permeability was reduced by 1.42-fold when the monolayers were treated with both TNF¿/CHX and InM simvastatin, relative to treatment with TNF¿/CHX only. Overall these results demonstrate the potential of manipulating endothelial monolayer permeability to LDL by altering the rate of apoptosis pharmacologically. This has implications for the treatment of vascular disease.