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Originally published In Press as doi:10.1194/jlr.M500177-JLR200 on August 1, 2005

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Journal of Lipid Research, Vol. 46, 2083-2090, October 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Apolipoprotein E inhibition of vascular hyperplasia and neointima formation requires inducible nitric oxide synthase

Zachary W. Q. Moore and David Y. Hui1

Department of Pathology and Laboratory Medicine, Genome Research Institute, University of Cincinnati College of Medicine, Cincinnati, OH

Published, JLR Papers in Press, August 1, 2005. DOI 10.1194/jlr.M500177-JLR200

1 To whom correspondence should be addressed. e-mail: huidy{at}email.uc.edu

Previous studies have shown apolipoprotein E (apoE) recruitment to medial layers of carotid arteries after vascular injury in vivo and apoE activation of inducible nitric oxide synthase (iNOS) in smooth muscle cells in vitro. This investigation explored the relationship between medial apoE recruitment and iNOS activation in protection against neointimal hyperplasia. ApoE was present in both neointimal-resistant C57BL/6 mice and neointimal-susceptible FVB/N mice 24 h after carotid denudation, but iNOS expression was observed only in the neointimal-resistant C57BL/6 mice. However, iNOS was not observed in apoE-defective C57BL/6 mice. In contrast, overexpression of apoE in FVB/N mice activated iNOS expression in the injured vessels, resulting in protection against neointimal hyperplasia. ApoE and iNOS were colocalized in the medial layer of neointimal-resistant mouse strains. Endothelial denudation of carotid arteries in the iNOS-deficient NOS2–/– mice did not increase neointimal hyperplasia but significantly increased medial thickness and area. The iNOS-specific inhibitor also abrogated the apoE protective effects on vascular response to injury in apoE-overexpressing FVB/N mice.

Thus, injury-induced activation of iNOS requires apoE recruitment. Moreover, both apoE and iNOS are necessary for the suppression of cell proliferation, and apoE recruitment without iNOS expression resulted in medial hyperplasia without cell migration to the intima.

Abbreviations: apoE, apolipoprotein E; COX-2, cyclooxygenase-2; iNOS, inducible nitric oxide synthase; LRP-1, low density lipoprotein receptor-related protein-1

Supplementary key words neointimal hyperplasia • smooth muscle cells • endothelial denudation • vascular biology • transgenic mice


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