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Intranasal delivery of E-selectin reduces atherosclerosis in ApoE-/- mice.

Li X, Johnson KR, Bryant M, Elkahloun AG, Amar M, Remaley AT, De Silva R, Hallenbeck JM, Quandt JA - PLoS ONE (2011)

Bottom Line: A reduction in inflammation and neural damage was associated with immunomodulatory or "tolerogenic" responses to E-selectin.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.

View Article: PubMed Central - PubMed

Affiliation: Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.

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.

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Intranasal delivery of E-selectin reduces atherosclerosis.Mice treated with regimen A (N = 5 per group) or regimen B (N = 10 per group) were processed En Face after 7 weeks on a high-fat diet. The lipid lesions in the aorta were stained with Sudan IV. (A) Representative photos illustrate the predominance of lesions in the aortic arch. (B) Quantification of lipid lesion on the ascending aorta and arch. In regimen B, pre-tolerization with E-selectin caused a significant 26.4% plaque reduction in the surface area of the ascending aorta and arch. (C) Movat staining of cross-sections of the aortic root in regimen B. The PBS and E-selectin groups showed similar degrees of pathology in the aortic roots.
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pone-0020620-g003: Intranasal delivery of E-selectin reduces atherosclerosis.Mice treated with regimen A (N = 5 per group) or regimen B (N = 10 per group) were processed En Face after 7 weeks on a high-fat diet. The lipid lesions in the aorta were stained with Sudan IV. (A) Representative photos illustrate the predominance of lesions in the aortic arch. (B) Quantification of lipid lesion on the ascending aorta and arch. In regimen B, pre-tolerization with E-selectin caused a significant 26.4% plaque reduction in the surface area of the ascending aorta and arch. (C) Movat staining of cross-sections of the aortic root in regimen B. The PBS and E-selectin groups showed similar degrees of pathology in the aortic roots.

Mentions: We assessed atherosclerosis in En Face sections after 7 weeks on a high-fat diet. Consistent with other studies in mouse models of atherosclerosis, the majority of the lipid lesions were located near the aortic root and arch. In regimen B, 52.0±2.7% of the surface area of the ascending aorta and arch were covered with atherosclerotic lesions in PBS group, yet pre-tolerization with E-selectin caused a significant 26.4% plaque reduction (38.2±4.5% of the ascending aorta and arch, P = 0.02) (Figure 3A and B). Regimen A was less effective at reducing the atherosclerosis on the ascending aorta and arch (40.4±10.0% in PBS group versus 24.6±8.8% in E-selectin group, P = 0.27).


Intranasal delivery of E-selectin reduces atherosclerosis in ApoE-/- mice.

Li X, Johnson KR, Bryant M, Elkahloun AG, Amar M, Remaley AT, De Silva R, Hallenbeck JM, Quandt JA - PLoS ONE (2011)

Intranasal delivery of E-selectin reduces atherosclerosis.Mice treated with regimen A (N = 5 per group) or regimen B (N = 10 per group) were processed En Face after 7 weeks on a high-fat diet. The lipid lesions in the aorta were stained with Sudan IV. (A) Representative photos illustrate the predominance of lesions in the aortic arch. (B) Quantification of lipid lesion on the ascending aorta and arch. In regimen B, pre-tolerization with E-selectin caused a significant 26.4% plaque reduction in the surface area of the ascending aorta and arch. (C) Movat staining of cross-sections of the aortic root in regimen B. The PBS and E-selectin groups showed similar degrees of pathology in the aortic roots.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3119064&req=5

pone-0020620-g003: Intranasal delivery of E-selectin reduces atherosclerosis.Mice treated with regimen A (N = 5 per group) or regimen B (N = 10 per group) were processed En Face after 7 weeks on a high-fat diet. The lipid lesions in the aorta were stained with Sudan IV. (A) Representative photos illustrate the predominance of lesions in the aortic arch. (B) Quantification of lipid lesion on the ascending aorta and arch. In regimen B, pre-tolerization with E-selectin caused a significant 26.4% plaque reduction in the surface area of the ascending aorta and arch. (C) Movat staining of cross-sections of the aortic root in regimen B. The PBS and E-selectin groups showed similar degrees of pathology in the aortic roots.
Mentions: We assessed atherosclerosis in En Face sections after 7 weeks on a high-fat diet. Consistent with other studies in mouse models of atherosclerosis, the majority of the lipid lesions were located near the aortic root and arch. In regimen B, 52.0±2.7% of the surface area of the ascending aorta and arch were covered with atherosclerotic lesions in PBS group, yet pre-tolerization with E-selectin caused a significant 26.4% plaque reduction (38.2±4.5% of the ascending aorta and arch, P = 0.02) (Figure 3A and B). Regimen A was less effective at reducing the atherosclerosis on the ascending aorta and arch (40.4±10.0% in PBS group versus 24.6±8.8% in E-selectin group, P = 0.27).

Bottom Line: A reduction in inflammation and neural damage was associated with immunomodulatory or "tolerogenic" responses to E-selectin.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.

View Article: PubMed Central - PubMed

Affiliation: Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.

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.

Show MeSH
Related in: MedlinePlus