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 adenoviraldriven 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.

ApoE Receptor 2 Mediation of Trophoblast Dysfunction and Pregnancy Complications Induced by Antiphospholipid Antibodies in Mice

“…In that manner the current findings extend our understanding of the biology of apoER2 beyond its well-established role in CNS development and Alzheimer’s disease (30) and its recently revealed functions in endothelium (26;29). Immunohistochemical analysis of human placenta revealed that apoER2 is abundantly expressed in trophoblasts throughout gestation, and immunoblotting demonstrated that the receptor is also expressed in HTR-8/SVneo and SW.71 cells that retain the characteristics of trophoblasts in culture (33;34;36).…”

“…In another recent study we discovered that apoER2 in endothelium also mediate responses to apolipoprotein E3 that are beneficial to cardiovascular health (29), highlighting the complexities of apoER2 function even in a single cell type. The biology of apoER2 is best understood in neurons in which it is critically involved in central nervous system development and Alzheimer’s disease (30).…”

Genome-Wide Association Study for Muscle Fat Content and Abdominal Fat Traits in Common Carp (Cyprinus carpio)

“…Furthermore, lrp8 is also involved in other physiologically processes, e.g. lipid-raft sorting, endothelial cell migration and fetal growth [51,52]. In addition, Yao et al .…”

Apolipoprotein E Receptor 2 Mediates Activated Protein C–Induced Endothelial Akt Activation and Endothelial Barrier Stabilization

“…23, 24, 34–37 To explore the importance of endothelial ApoER2 for APC’s cytoprotective actions, we used EA.hy926 cells as an endothelial cell surrogate 38, 39 to study some of APC’s various activities. Extensive data in this report show that ApoER2 is required for APC’s cytoprotective and signaling activities in this cell line.…”