Further, since overexpression of SphK1 in Sphk2−/− mice rescued both the macrophage lysosomal dysfunctions and aggravation of atherosclerosis in the present study, it is unlikely that slightly enhanced activation of S1PR2 and S1PR3 by the elevated plasma S1P could account for aggravated atherosclerosis in Sphk2−/− mice. This evidence concerns the gene SPHK2 and atherosclerosis.