Functional Humanization of Mouse Alox15 Does Not Alter Early Vascular Lipid Deposition in ApoE-Deficient Mice

Arachidonic acid 15-lipoxygenases (ALOX15) have previously been implicated in atherogenesis, and functional inactivation of the Alox15 gene protected mice from arterial lipid deposition. However, translation of these results into humans was criticized since human and mouse ALOX15 orthologs exhibit distinct catalytic properties. We recently created Alox15 knock-in mice (Alox15ki/ki), which express an enzyme variant (Leu353Phe mutant) exhibiting a reaction specificity similar to that of human ALOX15. To make these animals athero-susceptible, we crossed them with ApoE−/− mice yielding Alox15ki/ki+ApoE−/− animals and compared the degree of hypercholesterolemia, the extent of arterial lipid deposition, and the expression patterns of inflammation-related genes with the corresponding parameters of age- and sex-matched outbred control animals (Alox15wt/wt + ApoE−/−) keeping the mice for different time periods on regular chow diet. Peritoneal macrophages of Alox15ki/ki + ApoE−/− mice oxygenated arachidonic acid mainly to the 15S-hydroperoxy derivative (15S-HpETE) and this data indicates systemic functional humanization of the reaction specificity of the Alox15 pathway. In 14- and 25-week-old animals of either sex, we observed consistent genotype-specific differences neither in the extent of aortic lipid deposition nor in the vascular expression patterns of inflammation-related gene products. This data suggests that the reaction specificity of Alox15 may not be of major relevance for early mouse atherogenesis.