Genome-wide studies showed that mutation in apoER2 (
apolipoprotein E receptor-2) is additive with ε4 polymorphism in the
APOE gene on
cardiovascular disease risk in humans.
ApoE or apoER2 deficiency also accelerates
atherosclerosis lesion
necrosis in hypercholesterolemic mice and promotes
neointima formation after
vascular injury. This study tests the hypothesis that
apoE and apoER2 modulate vascular occlusive diseases through distinct mechanisms. Approach and Results: Carotid endothelial denudation induced robust
neointima formation in both
apoE-/- and apoER2-deficient Lrp8-/- mice. The intima in
apoE-/- mice was rich in smooth muscle cells, but the intima in Lrp8-/- mice was cell-poor and rich in extracellular matrix. Vascular smooth muscle cells isolated from
apoE-/- mice were hyperplastic whereas Lrp8-/- smooth muscle cells showed reduced proliferation but responded robustly to TGF (
transforming growth factor)-β-induced
fibronectin synthesis indicative of a senescence-associated secretory phenotype, which was confirmed by increased β-
galactosidase activity, p16INK4a immunofluorescence, and number of multinucleated cells. Western blot analysis of cell cycle-associated
proteins showed that apoER2 deficiency promotes cell cycle arrest at the metaphase/anaphase. Coimmunoprecipitation experiments revealed that apoER2 interacts with the catalytic subunit of
protein phosphatase 2A. In the absence of apoER2, PP2A-C (
protein phosphatase 2A catalytic subunit) failed to interact with CDC20 (cell-division cycle
protein 20) thus resulting in inactive
anaphase-promoting complex and impaired cell cycle exit.
CONCLUSIONS: