Myeloid HMG-CoA (3-Hydroxy-3-Methylglutaryl-Coenzyme A) Reductase Determines Atherosclerosis by Modulating Migration of Macrophages

DOI Web Site 被引用文献2件 参考文献45件 オープンアクセス
  • Kent Sakai
    From the Division of Endocrinology and Metabolism, Department of Medicine (K.S., S.N., T.W., B.T., H. Yamazaki, A.T., S.T., D.Y., M.T., H. Yagyu, J.-i.O., S.I.), Jichi Medical University, Shimotsuke, Tochigi, Japan
  • Shuichi Nagashima
    From the Division of Endocrinology and Metabolism, Department of Medicine (K.S., S.N., T.W., B.T., H. Yamazaki, A.T., S.T., D.Y., M.T., H. Yagyu, J.-i.O., S.I.), Jichi Medical University, Shimotsuke, Tochigi, Japan
  • Tetsuji Wakabayashi
    From the Division of Endocrinology and Metabolism, Department of Medicine (K.S., S.N., T.W., B.T., H. Yamazaki, A.T., S.T., D.Y., M.T., H. Yagyu, J.-i.O., S.I.), Jichi Medical University, Shimotsuke, Tochigi, Japan
  • Bayasgalan Tumenbayar
    From the Division of Endocrinology and Metabolism, Department of Medicine (K.S., S.N., T.W., B.T., H. Yamazaki, A.T., S.T., D.Y., M.T., H. Yagyu, J.-i.O., S.I.), Jichi Medical University, Shimotsuke, Tochigi, Japan
  • Hiroko Hayakawa
    Department of Biochemistry (H.H., M.H., S.-i.T.), Jichi Medical University, Shimotsuke, Tochigi, Japan
  • Morisada Hayakawa
    Department of Biochemistry (H.H., M.H., S.-i.T.), Jichi Medical University, Shimotsuke, Tochigi, Japan
  • Tadayoshi Karasawa
    Division of Inflammation Research, Center for Molecular Medicine (T.K., M.T.), Jichi Medical University, Shimotsuke, Tochigi, Japan
  • Ken Ohashi
    Department of Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Bunkyo ward, Japan (K.O.).
  • Hisataka Yamazaki
    From the Division of Endocrinology and Metabolism, Department of Medicine (K.S., S.N., T.W., B.T., H. Yamazaki, A.T., S.T., D.Y., M.T., H. Yagyu, J.-i.O., S.I.), Jichi Medical University, Shimotsuke, Tochigi, Japan
  • Akihito Takei
    From the Division of Endocrinology and Metabolism, Department of Medicine (K.S., S.N., T.W., B.T., H. Yamazaki, A.T., S.T., D.Y., M.T., H. Yagyu, J.-i.O., S.I.), Jichi Medical University, Shimotsuke, Tochigi, Japan
  • Shoko Takei
    From the Division of Endocrinology and Metabolism, Department of Medicine (K.S., S.N., T.W., B.T., H. Yamazaki, A.T., S.T., D.Y., M.T., H. Yagyu, J.-i.O., S.I.), Jichi Medical University, Shimotsuke, Tochigi, Japan
  • Daisuke Yamamuro
    From the Division of Endocrinology and Metabolism, Department of Medicine (K.S., S.N., T.W., B.T., H. Yamazaki, A.T., S.T., D.Y., M.T., H. Yagyu, J.-i.O., S.I.), Jichi Medical University, Shimotsuke, Tochigi, Japan
  • Manabu Takahashi
    From the Division of Endocrinology and Metabolism, Department of Medicine (K.S., S.N., T.W., B.T., H. Yamazaki, A.T., S.T., D.Y., M.T., H. Yagyu, J.-i.O., S.I.), Jichi Medical University, Shimotsuke, Tochigi, Japan
  • Hiroaki Yagyu
    From the Division of Endocrinology and Metabolism, Department of Medicine (K.S., S.N., T.W., B.T., H. Yamazaki, A.T., S.T., D.Y., M.T., H. Yagyu, J.-i.O., S.I.), Jichi Medical University, Shimotsuke, Tochigi, Japan
  • Jun-ichi Osuga
    From the Division of Endocrinology and Metabolism, Department of Medicine (K.S., S.N., T.W., B.T., H. Yamazaki, A.T., S.T., D.Y., M.T., H. Yagyu, J.-i.O., S.I.), Jichi Medical University, Shimotsuke, Tochigi, Japan
  • Masafumi Takahashi
    Division of Inflammation Research, Center for Molecular Medicine (T.K., M.T.), Jichi Medical University, Shimotsuke, Tochigi, Japan
  • Shin-ichi Tominaga
    Department of Biochemistry (H.H., M.H., S.-i.T.), Jichi Medical University, Shimotsuke, Tochigi, Japan
  • Shun Ishibashi
    From the Division of Endocrinology and Metabolism, Department of Medicine (K.S., S.N., T.W., B.T., H. Yamazaki, A.T., S.T., D.Y., M.T., H. Yagyu, J.-i.O., S.I.), Jichi Medical University, Shimotsuke, Tochigi, Japan

抄録

<jats:sec> <jats:title>Objective—</jats:title> <jats:p>Inhibition of HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) is atheroprotective primarily by decreasing plasma LDL (low-density lipoprotein)-cholesterol. However, it is unknown whether inhibition of HMGCR in myeloid cells contributes to this atheroprotection. We sought to determine the role of myeloid HMGCR in the development of atherosclerosis.</jats:p> </jats:sec> <jats:sec> <jats:title>Approach and Results—</jats:title> <jats:p> We generated mice with genetically reduced <jats:italic>Hmgcr</jats:italic> in myeloid cells ( <jats:italic>Hmgcr</jats:italic> <jats:sup> <jats:italic>m−</jats:italic> </jats:sup> <jats:sup> <jats:italic>/m</jats:italic> </jats:sup> <jats:sup>−</jats:sup> ) using LysM (Cre) and compared various functions of their macrophages to those of <jats:italic>Hmgcr</jats:italic> <jats:sup> <jats:italic>fl/fl</jats:italic> </jats:sup> control mice. We further compared the extent of atherosclerosis in <jats:italic>Hmgcr</jats:italic> <jats:sup> <jats:italic>m</jats:italic> −/ <jats:italic>m</jats:italic> − </jats:sup> and <jats:italic>Hmgcr</jats:italic> <jats:sup> <jats:italic>fl/fl</jats:italic> </jats:sup> mice in the absence of <jats:italic>Ldlr</jats:italic> (LDL receptor). <jats:italic>Hmgcr</jats:italic> <jats:sup> <jats:italic>m</jats:italic> −/ <jats:italic>m</jats:italic> − </jats:sup> macrophages and granulocytes had significantly lower <jats:italic>Hmgcr</jats:italic> mRNA expression and cholesterol biosynthesis than <jats:italic>Hmgcr</jats:italic> <jats:sup> <jats:italic>fl/fl</jats:italic> </jats:sup> cells. In vitro, <jats:italic>Hmgcr</jats:italic> <jats:sup> <jats:italic>m</jats:italic> −/ <jats:italic>m</jats:italic> − </jats:sup> monocytes/macrophages had reduced ability to migrate, proliferate, and survive compared with <jats:italic>Hmgcr</jats:italic> <jats:sup> <jats:italic>fl/fl</jats:italic> </jats:sup> monocytes/macrophages. However, there was no difference in ability to adhere, phagocytose, store lipids, or polarize to M1 macrophages between the 2 types of macrophages. The amounts of plasma membrane–associated small GTPase proteins, such as RhoA (RAS homolog family member A), were increased in <jats:italic>Hmgcr</jats:italic> <jats:sup> <jats:italic>m</jats:italic> −/ <jats:italic>m</jats:italic> − </jats:sup> macrophages. In the setting of <jats:italic>Ldlr</jats:italic> deficiency, <jats:italic>Hmgcr</jats:italic> <jats:sup> <jats:italic>m</jats:italic> −/ <jats:italic>m</jats:italic> − </jats:sup> mice developed significantly smaller atherosclerotic lesions than <jats:italic>Hmgcr</jats:italic> <jats:sup> <jats:italic>fl/fl</jats:italic> </jats:sup> mice. However, there were no differences between the 2 types of mice either in plasma lipoprotein profiles or in the numbers of proliferating or apoptotic cells in the lesions in vivo. The in vivo migration of <jats:italic>Hmgcr</jats:italic> <jats:sup> <jats:italic>m</jats:italic> −/ <jats:italic>m</jats:italic> − </jats:sup> macrophages to the lesions was reduced compared with <jats:italic>Hmgcr</jats:italic> <jats:sup> <jats:italic>fl/fl</jats:italic> </jats:sup> macrophages. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>Genetic reduction of HMGCR in myeloid cells may exert atheroprotective effects primarily by decreasing the migratory activity of monocytes/macrophages to the lesions.</jats:p> </jats:sec>

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