Abstract 15934: Common Genetic Variants of Apolipoprotein E and Apolipoprotein E Receptor 2 Have Differential Impact on Endothelial Function
Cardiovascular disease (CVD) risk is greater in individuals harboring the apolipoprotein E4 (apoE) allele versus apoE3, and in those with the Apolipoprotein E receptor 2 (ApoER2) variant ApoER2-R952Q, and the increased risks are independent of changes in lipid profile. How apoE, ApoER2, and their genetic variants influence CVD is poorly understood. The present study determined how apoE and ApoER2 variants impact endothelial cell function. In cultured endothelial cells, recombinant apoE3 robustly stimulated endothelial NO synthase (eNOS) via activation of PI3 kinase/Akt, and it promoted endothelial cell migration. ApoER2, which is known primarily to govern neuron differentiation, was detected in endothelial cells by immunoblot analysis, and siRNA knockdown revealed that it is required for apoE3 activation of eNOS and endothelial cell migration. In contrast to apoE3, apoE4 did not activate eNOS or endothelial cell migration. In addition, apoE4 at equal as well as lower concentrations fully antagonized all endothelial responses to apoE3. In eNOS-expressing NIH-3T3 cells that lack endogenous ApoER2, the introduction of wild-type receptor yielded cells in which apoE3 activates eNOS; in contrast, ApoER2-R952Q was nonfunctional. In mice, whose endogenous apoE is structurally and functionally similar to human apoE3, carotid artery reendothelialization was dramatically impaired in ApoER2-/- versus ApoER2+/+ males. Furthermore, whereas adenoviral-driven human apoE3 expression in wild-type mice had no effect on reendothelialization, the introduction of human apoE4 caused dramatic impairment in reendothelialization. Moreover, although lipid profiles were similar, LDLR-/-;ApoER2-/- mice had markedly worse atherosclerosis than LDLR-/-;ApoER2+/+ mice. Thus, apoE3-induced signaling mediated by ApoER2 promotes endothelial NO production and repair, and apoE4 does not activate these processes and instead it potently antagonizes apoE3/ApoER2 action in endothelium. In addition, ApoER2-R952Q is incapable of mediating signal initiation by apoE3, and ApoER2 promotes reendothelialization and is atheroprotective in mice. These findings indicate that genetic variants of apoE and ApoER2 likely impact CVD by modifying endothelial function.
- © 2013 by American Heart Association, Inc.