title: Intranasal delivery of E-selectin reduces atherosclerosis in ApoE-/- mice.
abstract: Mucosal tolerance to E-selectin prevents stroke and protects against ischemic brain damage in experimental models of stroke studying healthy animals or spontaneously hypertensive stroke-prone rats. A reduction in inflammation and neural damage was associated with immunomodulatory or "tolerogenic" responses to E-selectin. The purpose of the current study on ApoE deficient mice is to assess the capacity of this stroke prevention innovation to influence atherosclerosis, a major underlying cause for ischemic strokes; human E-selectin is being translated as a potential clinical prevention strategy for secondary stroke. Female ApoE-/- mice received intranasal delivery of E-selectin prior to (pre-tolerization) or simultaneously with initiation of a high-fat diet. After 7 weeks on the high-fat diet, lipid lesions in the aorta, serum triglycerides, and total cholesterol were assessed as markers of atherosclerosis development. We also assessed E-selectin-specific antibodies and cytokine responses, in addition to inflammatory responses that included macrophage infiltration of the aorta and altered gene expression profiles of aortic mRNA. Intranasal delivery of E-selectin prior to initiation of high-fat chow decreased atherosclerosis, serum total cholesterol, and expression of the leucocyte chemoattractant CCL21 that is typically upregulated in atherosclerotic lesions of ApoE-/- mice. This response was associated with the induction of E-selectin specific cells producing the immunomodulatory cytokine IL-10 and immunosuppressive antibody isotypes. Intranasal administration of E-selectin generates E-selectin specific immune responses that are immunosuppressive in nature and can ameliorate atherosclerosis, a major risk factor for ischemic stroke. These results provide additional preclinical support for the potential of induction of mucosal tolerance to E-selectin to prevent stroke.
authors.affiliation: Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Xinhui
authors.initials: X
authors.lastname: Li
authors.forename: Kory R
authors.initials: KR
authors.lastname: Johnson
authors.forename: Mark
authors.initials: M
authors.lastname: Bryant
authors.forename: Abdel G
authors.initials: AG
authors.lastname: Elkahloun
authors.forename: Marcelo
authors.initials: M
authors.lastname: Amar
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
authors.forename: Ranil
authors.initials: R
authors.lastname: De Silva
authors.forename: John M
authors.initials: JM
authors.lastname: Hallenbeck
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Quandt
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001057:Apolipoproteins E; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D019040:E-Selectin / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use*; D005260:Female; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D051379:Mice; D008817:Mice, Mutant Strains; D012333:RNA, Messenger; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000097:blood; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood
chemical_list: D001057:Apolipoproteins E; D019040:E-Selectin; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10