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

Arterioscler Thromb Vasc Biol. 2016 Jun;36(6):1114-21. doi: 10.1161/ATVBAHA.116.307437. Epub 2016 Apr 21.

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.

Keywords: blood platelet; cell adhesion; endothelial cells; inflammation; leukocytes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / metabolism*
  • Aorta / pathology
  • Aortic Diseases / genetics
  • Aortic Diseases / metabolism*
  • Aortic Diseases / pathology
  • Apolipoproteins E / deficiency*
  • Apolipoproteins E / genetics
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • Blood Platelets / metabolism
  • Bone Marrow Transplantation
  • Diet, High-Fat
  • Disease Models, Animal
  • Disease Progression
  • Endothelial Cells / metabolism
  • Genetic Predisposition to Disease
  • Humans
  • Macrophages / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • P-Selectin / genetics
  • P-Selectin / metabolism*
  • Phenotype
  • Plaque, Atherosclerotic
  • Time Factors
  • Venous Thrombosis / genetics
  • Venous Thrombosis / metabolism

Substances

  • Apolipoproteins E
  • P-Selectin
  • SELP protein, human