Objective:
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, p16
INK4a
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:
This study showed that apoER2 participates in APC (anaphase-promoting complex)/CDC20 complex formation during mitosis, and its absence impedes cytokinesis abscission thereby accelerating premature cell senescence and vascular disease. This mechanism is distinct from apoE deficiency, which causes smooth muscle cell hyperplasia to accelerate vascular disease.
Nuclear localization of CPI-17, a protein phosphatase-1 inhibitor protein, affects histone H3 phosphorylation and corresponds to proliferation of cancer and smooth muscle cells
