title: 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: University of Michigan, Department of Internal Medicine, Cardiovascular Research Center, Ann Arbor, MI, USA.
authors: Wei
authors: W
authors: Luo
authors: Hui
authors: H
authors: Wang
authors: Miina K
authors: MK
authors: Ohman
authors: Chiao
authors: C
authors: Guo
authors: Kate
authors: K
authors: Shi
authors: Julia
authors: J
authors: Wang
authors: Daniel T
authors: DT
authors: Eitzman
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016026:Bone Marrow Transplantation; D004002:Clodronic Acid / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D019040:E-Selectin / Q000097:blood; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D036904:Leukocyte Rolling; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019007:P-Selectin / Q000097:blood; D013997:Time Factors
chemical_list: D000906:Antibodies; D001057:Apolipoproteins E; D016207:Cytokines; D019040:E-Selectin; D053583:Interleukin-1beta; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D004002:Clodronic Acid