Genetic variants of ApoE and ApoER2 differentially modulate endothelial function

Significance Why genetic variants of the circulating protein apolipoprotein E (apoE) or its receptor apoliprotein E receptor 2 (ApoER2) confer greater cardiovascular disease risk is poorly understood. We report that in endothelial cells, which are the guardian cells of the vascular wall, the most co...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2014-09, Vol.111 (37), p.13493-13498
Main Authors: Ulrich, Victoria, Konaniah, Eddy S., Herz, Joachim, Gerard, Robert D., Jung, Eunjeong, Yuhanna, Ivan S., Ahmed, Mohamed, Hui, David Y., Mineo, Chieko, Shaul, Philip W.
Format: Article
Language:English
Subjects:
3T3 Cells
Animals
apolipoprotein E
Apolipoprotein E3 - genetics
Apolipoprotein E4 - genetics
Apolipoproteins
Apolipoproteins E - genetics
Biological Sciences
Biological variation
Cardiovascular diseases
Carotid arteries
Carotid Arteries - metabolism
Cattle
Cell Adhesion
Cell adhesion & migration
Cell Movement
disease severity
Endothelial cells
Endothelial Cells - cytology
Endothelial Cells - metabolism
Endothelium
genetic variation
Genetics
Humans
LDL-Receptor Related Proteins - genetics
LDL-Receptor Related Proteins - metabolism
Medical genetics
Mice
Monocytes - cytology
Mutant Proteins - metabolism
Neointima
Neointima - metabolism
Nitric Oxide Synthase Type III - metabolism
Receptors
risk
Rodents
Small interfering RNA
T cell receptors
Transcriptional regulatory elements
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Summary:Significance Why genetic variants of the circulating protein apolipoprotein E (apoE) or its receptor apoliprotein E receptor 2 (ApoER2) confer greater cardiovascular disease risk is poorly understood. We report that in endothelial cells, which are the guardian cells of the vascular wall, the most common form of apoE, apoE3, activates ApoER2 to favorably impact endothelial function. The risk-enhancing apoE variant apoE4 lacks this capacity and instead inhibits apoE3–ApoER2 action, and a risk-conferring ApoER2 variant is nonfunctional in endothelium. Evidence is obtained in mice that the genetic variants adversely impact endothelial repair and related vascular disease severity. From these discoveries personalized treatment strategies may be developed to protect individuals with risk-altering apoE or ApoER2 variants, which comprise approximately 15% of the population.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1402106111