title: Genetic variants of ApoE and ApoER2 differentially modulate endothelial function.
abstract: It is poorly understood why there is greater cardiovascular disease risk associated with the apolipoprotein E4 (apoE) allele vs. apoE3, and also greater risk with the LRP8/apolipoprotein E receptor 2 (ApoER2) variant ApoER2-R952Q. Little is known about the function of the apoE-ApoER2 tandem outside of the central nervous system. We now report that in endothelial cells apoE3 binding to ApoER2 stimulates endothelial NO synthase (eNOS) and endothelial cell migration, and it also attenuates monocyte-endothelial cell adhesion. However, apoE4 does not stimulate eNOS or endothelial cell migration or dampen cell adhesion, and alternatively it selectively antagonizes apoE3/ApoER2 actions. The contrasting endothelial actions of apoE4 vs. apoE3 require the N-terminal to C-terminal interaction in apoE4 that distinguishes it structurally from apoE3. Reconstitution experiments further reveal that ApoER2-R952Q is a loss-of-function variant of the receptor in endothelium. Carotid artery reendothelialization is decreased in ApoER2(-/-) mice, and whereas adenoviral-driven apoE3 expression in wild-type mice has no effect, apoE4 impairs reendothelialization. Moreover, in a model of neointima formation invoked by carotid artery endothelial denudation, ApoER2(-/-) mice display exaggerated neointima development. Thus, the apoE3/ApoER2 tandem promotes endothelial NO production, endothelial repair, and endothelial anti-inflammatory properties, and it prevents neointima formation. In contrast, apoE4 and ApoER2-R952Q display dominant-negative action and loss of function, respectively. Thus, genetic variants of apoE and ApoER2 impact cardiovascular health by differentially modulating endothelial function.
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, and.
authors.forename: Victoria
authors.initials: V
authors.lastname: Ulrich
authors.affiliation: Department of Pathology, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Reading, OH 45215.
authors.forename: Eddy S
authors.initials: ES
authors.lastname: Konaniah
authors.affiliation: Departments of Molecular Genetics and.
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
authors.affiliation: Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; and.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Gerard
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, and.
authors.forename: Eunjeong
authors.initials: E
authors.lastname: Jung
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, and.
authors.forename: Ivan S
authors.initials: IS
authors.lastname: Yuhanna
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, and.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Department of Pathology, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Reading, OH 45215.
authors.forename: David Y
authors.initials: DY
authors.lastname: Hui
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, and chieko.mineo@utsouthwestern.edu philip.shaul@utsouthwestern.edu.
authors.forename: Chieko
authors.initials: C
authors.lastname: Mineo
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, and chieko.mineo@utsouthwestern.edu philip.shaul@utsouthwestern.edu.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Shaul
mesh_terms: D016475:3T3 Cells; D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics; D053327:Apolipoprotein E4 / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics*; D002339:Carotid Arteries / Q000378:metabolism; D002417:Cattle; D002448:Cell Adhesion; D002465:Cell Movement; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000166:cytology; D050505:Mutant Proteins / Q000378:metabolism; D058426:Neointima / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism
chemical_list: D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D026502:LDL-Receptor Related Proteins; D050505:Mutant Proteins; C098773:low density lipoprotein receptor-related protein 8; D052250:Nitric Oxide Synthase Type III