Myeloid HMG-CoA (3-Hydroxy-3-Methylglutaryl-Coenzyme A) Reductase Determines Atherosclerosis by Modulating Migration of Macrophages
-
- 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
Abstract
<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>
Journal
-
- Arteriosclerosis, Thrombosis, and Vascular Biology
-
Arteriosclerosis, Thrombosis, and Vascular Biology 38 (11), 2590-2600, 2018-11
Ovid Technologies (Wolters Kluwer Health)
- Tweet
Details 詳細情報について
-
- CRID
- 1360848661361515008
-
- ISSN
- 15244636
- 10795642
-
- Data Source
-
- Crossref
- KAKEN