P-Selectin Expressed by a Human SELP Transgene Is Atherogenic in Apolipoprotein E–Deficient Mice. Issue 6 (June 2016)

• Record Type: Journal Article
• Authors: Zhang, Nan; Liu, Zhenghui; Yao, Longbiao; Mehta-D'souza, Padmaja; McEver, Rodger P.
• Is Part Of: Arteriosclerosis, thrombosis, and vascular biology. Volume 36:Issue 6(2016)
• Publication Date: 2016-06
• Subjects: blood platelet -- cell adhesion -- endothelial cells -- inflammation -- leukocytes; Arteriosclerosis -- Periodicals; Thrombosis -- Periodicals; Blood-vessels -- Pathophysiology -- Periodicals; Electronic journals; 616.13
• DOI: 10.1161/ATVBAHA.116.307437
• Languages: English
• ISSNs: 1079-5642

Abstract

Abstract : 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, increase Selp transcripts and augment atherosclerosis in mice. However, they decrease SELP transcripts in humans, challenging assumptions that human P-selectin is atherogenic. We used mice expressing a human SELP transgene to examine the atherogenic role of P-selectin. Approach and Results—: We crossed apolipoprotein E–deficient ( Apoe −/− ) mice with Selp −/− mice or transgenic mice expressing the entire human SELP gene ( TgSELP +/− ). Aortas developed larger, macrophage-rich atheromas in Apoe −/− Selp −/− TgSELP +/− mice than in Apoe −/− Selp −/− mice after 8 or 16 weeks on a Western diet. Confocal microscopy of Apoe −/− 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-old Apoe −/− Selp −/− TgSELP +/− weanlings before atheromas developed. Furthermore, human SELP transcripts were ≈3-fold higher in aortas of Apoe −/− Selp +/− TgSELP +/− weanlings than in Selp +/− TgSELP +/− weanlings, whereas murine Selp and Sele transcripts were equivalent in weanlings of both genotypes. Human SELP transcripts in aortas of Apoe −/− Selp +/− TgSELP +/− mice remained nearly constant during 16 weeks on a Western diet, whereas murine Selp and Sele transcripts progressively increased. Bone marrow transplantation in Apoe −/− Selp −/− and Apoe −/− Selp −/− TgSELP +/− mice demonstrated that both platelets and endothelial cells must express human P-selectin to promote atherogenesis. Conclusions—: P-selectin expressed by human SELP is atherogenic in Apoe −/− mice, suggesting that P-selectin contributes to atherogenesis in humans. Abstract : Supplemental Digital Content is available in the text.