BubR1 Insufficiency Results in Decreased Macrophage Proliferation and Attenuated Atherogenesis in Apolipoprotein...

Budding uninhibited by benzimidazole-related 1 (BubR1), a cell cycle-related protein, is an essential component of the spindle checkpoint that regulates cell division. BubR1 insufficiency causes early aging-associated vascular phenotypes. We generated low-BubR1-expressing mutant (BubR1^L/L) and apolipoprotein E-deficient (ApoE^-/-) mice (BubR1^L/L-ApoE^-/- mice) to investigate the effects of BubR1 on atherosclerosis.

Eight-week-old male BubR1^L/L-ApoE^-/- mice and age-matched ApoE^-/- mice were used in this study. Atherosclerotic lesion development after being fed a high-cholesterol diet for 12 weeks was inhibited in BubR1^L/L-ApoE^-/- mice compared with ApoE^-/- mice, and was accompanied by decreased accumulation of macrophages. To address the relative contribution of BubR1 on bone marrow-derived cells compared with non-bone marrow-derived cells, we performed bone marrow transplantation in ApoE^-/- and BubR1^L/L-ApoE^-/- mice. Decreased BubR1 in bone marrow cells and non-bone marrow-derived cells decreased the atherosclerotic burden. In vitro assays indicated that decreased BubR1 expression impaired proliferation, but not migration, of bone marrow-derived macrophages.

BubR1 may represent a promising new target for regulating atherosclerosis.