P-Selectin Expressed by a Human SELP Transgene Is Atherogenic in Apolipoprotein E–Deficient Mice

Objective— During inflammation, P-selectin expressed on activated endothelial cells and platelets mediates rolling adhesion of leukocytes. Atherosclerosis-prone mice crossed with P-selectin–deficient (Selp −/− ) mice develop smaller lesions. Cytokines, such as tumor necrosis factor-α, increaseSelp transcripts and augment atherosclerosis in mice. However, they decreaseSELP transcripts in humans, challenging assumptions that human P-selectin is atherogenic. We used mice expressing a humanSELP transgene to examine the atherogenic role of P-selectin.Approach and Results— We crossed apolipoprotein E–deficient (Apoe −/− ) mice withSelp −/− mice or transgenic mice expressing the entire humanSELP gene (TgSELP +/− ). Aortas developed larger, macrophage-rich atheromas inApoe −/− Selp −/− TgSELP +/− mice than inApoe −/− Selp −/− mice after 8 or 16 weeks on a Western diet. Confocal microscopy ofApoe −/− Selp −/− TgSELP +/− aortas revealed staining for human P-selectin in endothelial cells overlying atheromas but not in lesional macrophages. We also observed staining for human P-selectin in aortic endothelial cells of 3- to 4-week-oldApoe −/− Selp −/− TgSELP +/− weanlings before atheromas developed. Furthermore, humanSELP transcripts were ≈3-fold higher in aortas ofApoe −/− Selp +/− TgSELP +/− weanlings than inSelp +/− TgSELP +/− weanlings, whereas murineSelp andSele transcripts were equivalent in weanlings of both genotypes. HumanSELP transcripts in aortas ofApoe −/− Selp +/− TgSELP +/− mice remained nearly constant during 16 weeks on a Western diet, whereas murineSelp andSele transcripts progressively increased. Bone marrow transplantation inApoe −/− Selp −/− andApoe −/− Selp −/− TgSELP +/− mice demonstrated that both platelets and endothelial cells must express human P-selectin to promote atherogenesis.Conclusions— P-selectin expressed by humanSELP is atherogenic inApoe −/− mice, suggesting that P-selectin contributes to atherogenesis in humans.