MafB promotes atherosclerosis by inhibiting foam-cell apoptosis.
MafB is a transcription factor that induces myelomonocytic differentiation. However, the precise role of MafB in the pathogenic function of macrophages has never been clarified. Here we demonstrate that MafB promotes hyperlipidemic atherosclerosis by suppressing foam-cell apoptosis. Our data show that MafB is predominantly expressed in foam cells found within atherosclerotic lesions, where MafB mediates the oxidized LDL-activated LXR/RXR-induced expression of apoptosis inhibitor of macrophages (AIM). In the absence of MafB, activated LXR/RXR fails to induce the expression of AIM, a protein that is normally responsible for protecting macrophages from apoptosis; thus, Mafb-deficient macrophages are prone to apoptosis. Haematopoietic reconstitution with Mafb-deficient fetal liver cells in recipient LDL receptor-deficient hyperlipidemic mice revealed accelerated foam-cell apoptosis, which subsequently led to the attenuation of the early atherogenic lesion. These findings represent the first evidence that the macrophage-affiliated MafB transcription factor participates in the acceleration of atherogenesis.
1] Department of Anatomy and Embryology, University of Tsukuba, 1-1-1, Tennodai, Ibaraki 305-8575, Japan [2] International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1, Tennodai, Tsukuba Ibaraki 305-8575, Japan [3] Laboratory Animal Resource Center (LARC), Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Ibaraki 305-8575, Japan [4].
Michito
M
Hamada
1] Department of Anatomy and Embryology, University of Tsukuba, 1-1-1, Tennodai, Ibaraki 305-8575, Japan [2].
Megumi
M
Nakamura
1] Department of Anatomy and Embryology, University of Tsukuba, 1-1-1, Tennodai, Ibaraki 305-8575, Japan [2] International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1, Tennodai, Tsukuba Ibaraki 305-8575, Japan.
Mai Thi Nhu
MT
Tran
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
Takashi
T
Moriguchi
Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, California 90095, USA.
Cynthia
C
Hong
Department of Anatomy and Embryology, University of Tsukuba, 1-1-1, Tennodai, Ibaraki 305-8575, Japan.
Takayuki
T
Ohsumi
1] Laboratory Animal Resource Center (LARC), Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Ibaraki 305-8575, Japan [2] Department of Experimental Pathology, University of Tsukuba, 1-1-1, Tennodai, Ibaraki 305-8575, Japan.
Tra Thi Huong
TT
Dinh
Department of Anatomy and Embryology, University of Tsukuba, 1-1-1, Tennodai, Ibaraki 305-8575, Japan.
Manabu
M
Kusakabe
Department of Anatomy and Embryology, University of Tsukuba, 1-1-1, Tennodai, Ibaraki 305-8575, Japan.
Motochika
M
Hattori
Department of Anatomy and Embryology, University of Tsukuba, 1-1-1, Tennodai, Ibaraki 305-8575, Japan.
Tokio
T
Katsumata
Division of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Satoko
S
Arai
Division of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Katsuhiko
K
Nakashima
1] Department of Anatomy and Embryology, University of Tsukuba, 1-1-1, Tennodai, Ibaraki 305-8575, Japan [2] International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1, Tennodai, Tsukuba Ibaraki 305-8575, Japan.
Takashi
T
Kudo
Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Etsushi
E
Kuroda
Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, No. 7 Jhong-Shan South Road, Taipei 100, Taiwan.
Chien-Hui
CH
Wu
Department of Dermatology, Chang Gung Memorial Hospital, No. 199, Tung-Hwa North Road, Taipei 100, Taiwan.
Pei-Han
PH
Kao
Department of Biomedical Science and Engineering, Faculty of Health Sciences, Hokkaido University, N12, W5, Kita-ku, Sapporo 060-0821, Japan.
Masaharu
M
Sakai
1] International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1, Tennodai, Tsukuba Ibaraki 305-8575, Japan [2] Department of Internal Medicine (Endocrinology and Metabolism), University of Tsukuba, 1-1-1, Tennodai, Ibaraki 305-8575, Japan.
Hitoshi
H
Shimano
Division of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Toru
T
Miyazaki
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
Peter
P
Tontonoz
1] Department of Anatomy and Embryology, University of Tsukuba, 1-1-1, Tennodai, Ibaraki 305-8575, Japan [2] International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1, Tennodai, Tsukuba Ibaraki 305-8575, Japan [3] Laboratory Animal Resource Center (LARC), Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Ibaraki 305-8575, Japan [4] Life Science Center, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, 1-1-1, Tennodai, Ibaraki 305-8575, Japan.
Satoru
S
Takahashi
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D050197:Atherosclerosis / Q000473:pathology / Q000503:physiopathology*; D001483:Base Sequence; D005487:Foam Cells / Q000473:pathology*; D006801:Humans; D000071518:Liver X Receptors; D051258:MafB Transcription Factor / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics; D051116:Receptors, Scavenger; D047488:Retinoid X Receptors / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid
D051017:Apoptosis Regulatory Proteins; C117272:Cd5l protein, mouse; D000071518:Liver X Receptors; D051258:MafB Transcription Factor; C490406:Mafb protein, mouse; D057093:Orphan Nuclear Receptors; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D047488:Retinoid X Receptors