P-Selectin Expressed by a Human SELP Transgene Is Atherogenic in Apolipoprotein E-Deficient Mice.
Arterioscler Thromb Vasc Biol
; 36(6): 1114-21, 2016 06.
Article
em En
| MEDLINE
| ID: mdl-27102967
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 ANDRESULTS:
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Aorta
/
Doenças da Aorta
/
Apolipoproteínas E
/
Selectina-P
/
Aterosclerose
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Arterioscler Thromb Vasc Biol
Assunto da revista:
ANGIOLOGIA
Ano de publicação:
2016
Tipo de documento:
Article