P-selectin glycoprotein ligand-1 deficiency leads to cytokine resistance and protection against atherosclerosis in apolipoprotein E deficient mice.

Abstract

Adhesive interactions between endothelial cells and leukocytes contribute to atherosclerotic plaque growth. However, mechanism(s) responsible for endothelial priming and deactivation in inflammatory diseases such as atherosclerosis are not clear. Apolipoprotein E deficient mice were generated with deficiency of P-selectin glycoprotein ligand-1 (Psgl-1(-/-), ApoE(-/-)). On both standard chow and Western diet, Psgl-1(-/-), ApoE(-/-) mice were protected against atherosclerosis compared to Psgl-1(+/+), ApoE(-/-) controls. Psgl-1(-/-), ApoE(-/-) mice also showed reduced leukocyte rolling and firm attachment on endothelial cells, however, adoptively transferred Psgl-1(+/+), ApoE(-/-) leukocytes into Psgl-1(-/-), ApoE(-/-) hosts displayed similar reduced rolling as Psgl-1(-/-), ApoE(-/-) leukocytes. Hematopoietic deficiency of Psgl-1 conferred resistance to the effects of interleukin-1β (IL-1β) on leukocyte rolling along with reduced circulating levels of sP-sel and sE-sel. Antibody blockade of Psgl-1 also reduced endothelial activation in response to IL-1β, eliminated leukocyte rolling, and was protective against atherosclerosis in ApoE(-/-) mice. Monocyte depletion with clodronate restored the endothelial response to IL-1β in Psgl-1(-/-) mice. This study suggests that Psgl-1 deficiency leads to reduced atherosclerosis and adhesive interactions between endothelial cells and leukocytes by indirectly regulating endothelial responses to cytokine stimulation.

• Authors: Wei Luo, Hui Wang, Miina K Ohman, Chiao Guo, Kate Shi, Julia Wang, Daniel T Eitzman
• Journal: Atherosclerosis (Atherosclerosis) Vol. 220 Issue 1 Pg. 110-7 (Jan 2012) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 22041028 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Ireland Ltd.

Chemical References

• Antibodies
• Apolipoproteins E
• Cytokines
• E-Selectin
• Interleukin-1beta
• Membrane Glycoproteins
• P-Selectin
• P-selectin ligand protein
• Clodronic Acid

Topics

• Adoptive Transfer
• Animals
• Antibodies (pharmacology)
• Apolipoproteins E (deficiency, genetics)
• Atherosclerosis (genetics, immunology, metabolism, pathology, prevention & control)
• Bone Marrow Transplantation
• Clodronic Acid (pharmacology)
• Cytokines (metabolism)
• Disease Models, Animal
• E-Selectin (blood)
• Endothelial Cells (drug effects, immunology, metabolism, pathology)
• Interleukin-1beta (metabolism)
• Leukocyte Rolling
• Leukocytes (drug effects, immunology, metabolism)
• Membrane Glycoproteins (antagonists & inhibitors, deficiency, genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Monocytes (drug effects, immunology, metabolism)
• P-Selectin (blood)
• Time Factors