Although the genetic absence of Nos3 in Apoe−/− mice is known to exacerbate atherosclerosis, which reflects the anti-atherosclerotic role of eNOS-derived NO49,50, Nos3 overexpression is also unexpectedly found to promote atherogenesis as a result of eNOS uncoupling, which is caused by a lack of the eNOS cofactor, BH451,52. This evidence concerns the gene APOE and atherosclerosis.