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Myeloid HMG-CoA (3-Hydroxy-3-Methylglutaryl-Coenzyme A) Reductase Determines Atherosclerosis by Modulating Migration of Macrophages.
Sakai, Kent; Nagashima, Shuichi; Wakabayashi, Tetsuji; Tumenbayar, Bayasgalan; Hayakawa, Hiroko; Hayakawa, Morisada; Karasawa, Tadayoshi; Ohashi, Ken; Yamazaki, Hisataka; Takei, Akihito; Takei, Shoko; Yamamuro, Daisuke; Takahashi, Manabu; Yagyu, Hiroaki; Osuga, Jun-Ichi; Takahashi, Masafumi; Tominaga, Shin-Ichi; Ishibashi, Shun.
Afiliação
  • Sakai K; 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.
  • Nagashima S; 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.
  • Wakabayashi T; 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.
  • Tumenbayar B; 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.
  • Hayakawa H; Department of Biochemistry (H.H., M.H., S.-i.T.), Jichi Medical University, Shimotsuke, Tochigi, Japan.
  • Hayakawa M; Department of Biochemistry (H.H., M.H., S.-i.T.), Jichi Medical University, Shimotsuke, Tochigi, Japan.
  • Karasawa T; Division of Inflammation Research, Center for Molecular Medicine (T.K., M.T.), Jichi Medical University, Shimotsuke, Tochigi, Japan.
  • Ohashi K; Department of Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Bunkyo ward, Japan (K.O.).
  • Yamazaki H; 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.
  • Takei A; 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.
  • Takei S; 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.
  • Yamamuro D; 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.
  • Takahashi M; 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.
  • Yagyu H; 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.
  • Osuga JI; 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.
  • Takahashi M; Division of Inflammation Research, Center for Molecular Medicine (T.K., M.T.), Jichi Medical University, Shimotsuke, Tochigi, Japan.
  • Tominaga SI; Department of Biochemistry (H.H., M.H., S.-i.T.), Jichi Medical University, Shimotsuke, Tochigi, Japan.
  • Ishibashi S; 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.
Arterioscler Thromb Vasc Biol ; 38(11): 2590-2600, 2018 11.
Article em En | MEDLINE | ID: mdl-30354246
Objective- 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. Approach and Results- We generated mice with genetically reduced Hmgcr in myeloid cells ( Hmgcr m-/m-) using LysM (Cre) and compared various functions of their macrophages to those of Hmgcr fl/fl control mice. We further compared the extent of atherosclerosis in Hmgcr m-/ m- and Hmgcr fl/fl mice in the absence of Ldlr (LDL receptor). Hmgcr m-/ m- macrophages and granulocytes had significantly lower Hmgcr mRNA expression and cholesterol biosynthesis than Hmgcr fl/fl cells. In vitro, Hmgcr m-/ m- monocytes/macrophages had reduced ability to migrate, proliferate, and survive compared with Hmgcr fl/fl 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 Hmgcr m-/ m- macrophages. In the setting of Ldlr deficiency, Hmgcr m-/ m- mice developed significantly smaller atherosclerotic lesions than Hmgcr fl/fl 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 Hmgcr m-/ m- macrophages to the lesions was reduced compared with Hmgcr fl/fl macrophages. Conclusions- Genetic reduction of HMGCR in myeloid cells may exert atheroprotective effects primarily by decreasing the migratory activity of monocytes/macrophages to the lesions.
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Texto completo: 1 Coleções: 01-internacional Contexto em Saúde: 1_ASSA2030 Base de dados: MEDLINE Assunto principal: Aorta / Doenças da Aorta / Monócitos / Movimento Celular / Macrófagos Peritoneais / Aterosclerose / Hidroximetilglutaril-CoA Redutases Limite: Animals Idioma: En Revista: Arterioscler Thromb Vasc Biol Ano de publicação: 2018 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Contexto em Saúde: 1_ASSA2030 Base de dados: MEDLINE Assunto principal: Aorta / Doenças da Aorta / Monócitos / Movimento Celular / Macrófagos Peritoneais / Aterosclerose / Hidroximetilglutaril-CoA Redutases Limite: Animals Idioma: En Revista: Arterioscler Thromb Vasc Biol Ano de publicação: 2018 Tipo de documento: Article