Contribution of Lysosomes to the Formation of Lipid raft‐redox Signaling Platforms in Coronary Arterial Endothelial Cells

The formation of lipid raft (LR)‐redox signaling platforms on coronary arterial endothelial cell (CAEC) membrane is an important mechanism mediating transmembrane signaling of different death receptors and thereby resulting in endothelial dysfunction. This platform formation was associated with activation of acid sphingomyelinase (ASM). Given that lysosomal ASM is a major type of ASM, the present study tested whether lysosome function contributes to this process. By confocal microscopic analysis, we found that Fas ligand (Fas L) stimulated the clustering of individual LRs on the plasma membrane of CAECs and induced the aggregation of NAD(P)H oxidase complex subunits, gp91 phox and p47 phox to LR clusters. When the cells were pretreated with the lysosome function inhibitors, bafilomycin and GPN, Fas L‐induced LR redox signaling platform formation was markedly abolished. Correspondingly, superoxide (O 2 −. ) production induced by Fas L was significantly decreased by lysosomal function inhibition. In isolated perfused small coronary arteries, Fas L‐induced inhibition of endothelium‐dependent vasorelaxation was also reduced by inhibition of lysosome function. These results demonstrate that lysosome function plays an important role in the formation of LR‐redox signaling platforms and that inhibition of lysosome function may protect coronary artery from death receptor‐mediated endothelial dysfunction (Supported by NIH Grants HL57244 and HL70726).