Abstract
We addressed the role of caveolin-1, the principal structural and signaling molecule of caveolae, in the regulation of endothelial cell oxidant generation. Using cultured mouse lung vascular endothelial cells from wild-type (WT) and caveolin-1 knockout (Cav-1−/−) mice, we observed that the TNFa-induced generation of superoxide anion, as measured by dihydroethidium staining, was abrogated in cells isolated from Cav-1−/− mice. Similarly, human pulmonary artery endothelial cells transfected with caveolin-1 siRNA demonstrated marked reduction in superoxide production compared to cells transfected with control vector and mutant construct. To elucidate mechanisms of caveolin-1 regulation of oxidant generation, we co-immunoprecipitated caveolin-1 with proteins involved in assembly of the NADPH oxidase complex. We found that caveolin-1 co-immunoprecipitated with Rac-1 following TNFa stimulation. We also investigated the effect of caveolin-1 suppression on oxidant signaling by assaying downstream signals of inflammation in the endothelial cell. We found that siRNA knockdown of caveolin-1 reduced TNFa-induced NF-kB activation. Thus, caveolin-1 may regulate oxidant generation by promoting the assembly of components of the NADPH complex, and thereby activate oxidant signaling in endothelial cells.
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