BubR1 Insufficiency Results in Decreased Macrophage Proliferation and Attenuated Atherogenesis in Apolipoprotein E-Deficient Mice.
BACKGROUND
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 (BubR1L/L) and apolipoprotein E-deficient (ApoE-/-) mice (BubR1L/L-ApoE-/-mice) to investigate the effects of BubR1 on atherosclerosis.


RESULTS
Eight-week-old male BubR1L/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 BubR1L/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 BubR1L/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.


CONCLUSIONS
BubR1 may represent a promising new target for regulating atherosclerosis.
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan R&D Laboratory for Innovative Biotherapeutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Shinichi
S
Tanaka
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan takum@surg2.med.kyushu-u.ac.jp.
Takuya
T
Matsumoto
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Yutaka
Y
Matsubara
R&D Laboratory for Innovative Biotherapeutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Yui
Y
Harada
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Ryoichi
R
Kyuragi
Department of Cardiovascular Research, Development, and Translational Medicine, Kyushu University, Fukuoka, Japan.
Jun-Ichiro
JI
Koga
Department of Cardiovascular Research, Development, and Translational Medicine, Kyushu University, Fukuoka, Japan.
Kensuke
K
Egashira
Division of Pathology, Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan.
Yutaka
Y
Nakashima
R&D Laboratory for Innovative Biotherapeutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Yoshikazu
Y
Yonemitsu
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Yoshihiko
Y
Maehara
atherosclerosis; cell cycle; macrophage; proliferation
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