NOS3 and endothelial dysfunction: Overexpression of p66shc inhibited Ras-PI3K-Akt-eNOS/NO pathways, while knockdown of p66shc increased eNOS phosphorylation at S1177 and NO production, decreased O2− production, protecting against endothelial dysfunction induced by age and oxidized low-density lipoprotein (ox-LDL) [39, 40].