We propose that the loss of soluble ACE2 may also be an important and independent determinant of the Ace2 knockout phenotype, as in this study, we show that restoration of soluble ACE2 to physiological levels in Ace2/ApoE DKO mice can prevent the characteristic acceleration of atherosclerosis usually seen in this model and can be prevented even without restoration of tissue ACE2. This evidence concerns the gene APOE and atherosclerosis.