Apolipoprotein E Enhances Endothelial-NO Production by Modulating Caveolin 1 Interaction With Endothelial NO Synthase

Yue, Lili; Bian, Jing; Grizelj, Ivana; Čavka, Ana; Phillips, Shane A.; Makino, Ayako; Mazzone, Theodore

doi:10.1161/hypertensionaha.112.196667

Cited by 36 publications

(33 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S1). These findings are consistent with the previous observations that apoE3 promotes NO release from human umbilical vein endothelial cells and from EA.hy926 endothelial-epithelial hybrid cells (15,16). A key role for ApoER2 in the apoE3 mechanism of action in endothelial cells was then demonstrated for the first time (to our knowledge) by the finding that siRNA-based depletion of the receptor in BAEC (Fig.…”

Section: Resultssupporting

confidence: 93%

Genetic variants of ApoE and ApoER2 differentially modulate endothelial function

Ulrich

Konaniah

Herz³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

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.

show abstract

Section: Resultssupporting

confidence: 93%

Genetic variants of ApoE and ApoER2 differentially modulate endothelial function

Ulrich

Konaniah

Herz³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The additional genes from GSEA include CHRNA2 encoding the neuronal cholinergic receptor, nicotinic, alpha 2 and RAPSN , the receptor-associated protein of the synapse, both of which appear in the synaptic transmission, cholinergic pathway (Supplementary Table 13). CAV1 encodes caveolin 1 which can interact with APOE[26] and is found in caveolae, areas of cholesterol-rich lipid raft involved in endocytosis. CACNA1D encodes the calcium channel, voltage-dependent, L type, alpha 1D subunit, one of a series of alpha subunits that confer channel-specific properties, influences insulin secretion and is a risk gene for type 2 diabetes[27].…”

Section: Discussionmentioning

confidence: 99%

Convergent genetic and expression data implicate immunity in Alzheimer's disease

Jones¹,

Lambert²,

Wang³

et al. 2014

Alzheimer's & Dementia

178

View full text Add to dashboard Cite

Background Late–onset Alzheimer's disease (AD) is heritable with 20 genes showing genome wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease we extended these genetic data in a pathway analysis. Methods The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (p = 3.27×10-12 after multiple testing correction for pathways), regulation of endocytosis (p = 1.31×10-11), cholesterol transport (p = 2.96 × 10-9) and proteasome-ubiquitin activity (p = 1.34×10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected p 0.002 – 0.05). Conclusions The immune response, regulation of endocytosis, cholesterol transport and protein ubiquitination represent prime targets for AD therapeutics.

show abstract

“…For example, apoE produced by macrophages relieves the inhibition of eNOS by caveolin in endothelial cells by displacing the caveolin from its complex with the NO synthase (87). Exogenous apoE inhibits macrophage activation by TLR3 and TLR4 agonists through distinct mechanisms (88).…”

Section: Coronary Atherosclerosis and Myocardial Infarction Inmentioning

confidence: 99%

ApoE knockout and knockin mice: the history of their contribution to the understanding of atherogenesis

Getz

Reardon

2016

Journal of Lipid Research

View full text Add to dashboard Cite

Human apoE is found in the plasma associated with VLDL and HDL. It is a 34 kDa protein that is posttranslationally modified, mostly by glycosylation. The mature protein contains 299 amino acids and is encoded on chromosome 19. The gene was first sequenced in 1985 (5). The mouse protein is 70% homologous. apoE is the primary ligand for the removal of chylomicron remnants and intermediate density lipoproteins by the liver, functioning to ligate these particles to the LDL receptor (LDLR) and the LDLR-related protein 1 (LRP-1) (6).The understanding of the physiological role of apoE was greatly enhanced by the study of type III hyperlipoproteinemia. Type III hyperlipoproteinemia presents clinically as hypercholesterolemia and hypertriglyceridemia with the presence of cholesterol-enriched VLDL and a high likelihood of premature ischemic heart disease and peripheral vascular disease, as well as xanthomata, especially palmar xanthomata (7). This abnormal VLDL is the result of impaired clearance of remnant lipoproteins; initially demonstrated by the clearance of injected radiolabeled apoB48-and apoB100-containing lipoproteins in these dyslipidemic patients (8). Indeed, the genetics of type III hyperlipoproteinemia or dysfunctional hyperlipoproteinemia revealed the allelic polymorphism of human apoE, initially reported by Utermann, Hees, and Steinmetz (9). This study identified two allelic forms that were designated as E-N for normal apoE and E-D for dysfunctional apoE, with the E-D isoform prevalent in patients with type III hyperlipoproteinemia. Further study of the genetics of the apoE isoforms identified three common allelic variants, E2 (equivalent to the E-D allele), E3 (equivalent to the E-N allele), and E4, encoding apoE2, apoE3, and apoE4, respectively (10). The allele frequencies are 4-13%, 75-85%, and 14-23% for E2, E3, and E4, respectively. APOE2 homozygotes are found in about 2-5% of the human Abstract ApoE is a multifunctional protein that is expressed by many cell types that influences many aspects of cardiovascular physiology. In humans, there are three major allelic variants that differentially influence lipoprotein metabolism and risk for the development of atherosclerosis. Apoe-deficient mice and human apoE isoform knockin mice, as well as hypomorphic Apoe mice, have significantly contributed to our understanding of the role of apoE in lipoprotein metabolism, monocyte/macrophage biology, and atherosclerosis. This brief history of these mouse models will highlight their contribution to the understanding of the role of apoE in these processes. These Apoe / mice have also been extensively utilized as an atherosensitive platform upon which to assess the impact of modulator genes on the development and regression of atherosclerosis. "A golden age for experimental atherosclerosis dawned when Nobuyo Maeda and Jan Breslow knocked out the Apoe gene in mice" (ref. 1, p. 386). These seminal studies were published in 1992, but were preceded by almost 20 years of experimentation on the structure/function of...

show abstract

Apolipoprotein E Enhances Endothelial-NO Production by Modulating Caveolin 1 Interaction With Endothelial NO Synthase

Cited by 36 publications

References 41 publications

Genetic variants of ApoE and ApoER2 differentially modulate endothelial function

Genetic variants of ApoE and ApoER2 differentially modulate endothelial function

Convergent genetic and expression data implicate immunity in Alzheimer's disease

ApoE knockout and knockin mice: the history of their contribution to the understanding of atherogenesis

Contact Info

Product

Resources

About