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



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.



P-selectin expressed by human SELP is atherogenic in Apoe(-/-) mice, suggesting that P-selectin contributes to atherogenesis in humans.
From the Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City (N.Z., R.P.M.); and Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City (Z.L., L.Y., P.M.-D., R.P.M.).
Nan
N
Zhang
From the Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City (N.Z., R.P.M.); and Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City (Z.L., L.Y., P.M.-D., R.P.M.).
Zhenghui
Z
Liu
From the Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City (N.Z., R.P.M.); and Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City (Z.L., L.Y., P.M.-D., R.P.M.).
Longbiao
L
Yao
From the Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City (N.Z., R.P.M.); and Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City (Z.L., L.Y., P.M.-D., R.P.M.).
Padmaja
P
Mehta-D'souza
From the Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City (N.Z., R.P.M.); and Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City (Z.L., L.Y., P.M.-D., R.P.M.). rodger-mcever@omrf.org.
Rodger P
RP
McEver
D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001792:Blood Platelets / Q000378:metabolism; D016026:Bone Marrow Transplantation; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D013997:Time Factors; D020246:Venous Thrombosis / Q000235:genetics / Q000378:metabolism
D001057:Apolipoproteins E; D019007:P-Selectin; C546937:SELP protein, human
blood platelet; cell adhesion; endothelial cells; inflammation; leukocytes