Myeloid HMG-CoA (3-Hydroxy-3-Methylglutaryl-Coenzyme A) Reductase Determines Atherosclerosis by Modulating Migration of Macrophages
Myeloid HMG-CoA (3-Hydroxy-3-Methylglutaryl-Coenzyme A) Reductase Determines Atherosclerosis by Modulating Migration of Macrophages
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DOI：
10.1161/atvbaha.118.311664
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发表时间：
2018-08
期刊：
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通讯作者：
Kent Sakai;Shuichi Nagashima;Tetsuji Wakabayashi;Bayasgalan Tumenbayar;Hiroko Hayakawa;M. Hayakawa;Tadayoshi Karasawa;K. Ohashi;Hisataka Yamazaki;Akihito Takei;Shoko Takei;D. Yamamuro;Manabu Takahashi;H. Yagyu;J. Osuga;Masafumi Takahashi;S. Tominaga;S. Ishibashi
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作者：
Kent Sakai;Shuichi Nagashima;Tetsuji Wakabayashi;Bayasgalan Tumenbayar;Hiroko Hayakawa;M. Hayakawa;Tadayoshi Karasawa;K. Ohashi;Hisataka Yamazaki;Akihito Takei;Shoko Takei;D. Yamamuro;Manabu Takahashi;H. Yagyu;J. Osuga;Masafumi Takahashi;S. Tominaga;S. Ishibashi
目的——抑制 HMGCR（3-羟基-3-甲基戊二酰辅酶 A 还原酶）主要通过降低血浆 LDL（低密度脂蛋白）胆固醇来预防动脉粥样硬化。然而，尚不清楚抑制骨髓细胞中的 HMGCR 是否有助于这种动脉粥样硬化保护。我们试图确定骨髓 HMGCR 在动脉粥样硬化发展中的作用。方法和结果——我们使用 LysM (Cre) 生成了骨髓细胞中 Hmgcr 基因降低的小鼠 (Hmgcrm−/m−)，并将其巨噬细胞的各种功能与 Hmgcrfl/fl 对照小鼠进行了比较。我们进一步比较了在缺乏 Ldlr（LDL 受体）的情况下 Hmgcrm−/m− 和 Hmgcrfl/fl 小鼠的动脉粥样硬化程度。 Hmgcrm−/m− 巨噬细胞和粒细胞的 Hmgcr mRNA 表达和胆固醇生物合成显着低于 Hmgcrfl/fl 细胞。在体外，与 Hmgcrfl/fl 单核细胞/巨噬细胞相比，Hmgcrm−/m− 单核细胞/巨噬细胞的迁移、增殖和存活能力降低。然而，两种类型的巨噬细胞粘附、吞噬、储存脂质或极化 M1 巨噬细胞的能力没有差异。 Hmgcrm−/m− 巨噬细胞中质膜相关的小 GTP 酶蛋白（例如 RhoA（RAS 同源家族成员 A））的数量增加。在 Ldlr 缺乏的情况下，Hmgcrm−/m− 小鼠产生的动脉粥样硬化病变明显小于 Hmgcrfl/fl 小鼠。然而，两种类型的小鼠之间无论是血浆脂蛋白谱还是体内病灶中增殖或凋亡细胞的数量都没有差异。与 Hmgcrfl/fl 巨噬细胞相比，Hmgcrm−/m− 巨噬细胞向病变的体内迁移减少。结论：骨髓细胞中 HMGCR 的遗传减少可能主要通过降低单核细胞/巨噬细胞向病变的迁移活性来发挥动脉粥样硬化保护作用。
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 (Hmgcrm−/m−) using LysM (Cre) and compared various functions of their macrophages to those of Hmgcrfl/fl control mice. We further compared the extent of atherosclerosis in Hmgcrm−/m− and Hmgcrfl/fl mice in the absence of Ldlr (LDL receptor). Hmgcrm−/m− macrophages and granulocytes had significantly lower Hmgcr mRNA expression and cholesterol biosynthesis than Hmgcrfl/fl cells. In vitro, Hmgcrm−/m− monocytes/macrophages had reduced ability to migrate, proliferate, and survive compared with Hmgcrfl/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 Hmgcrm−/m− macrophages. In the setting of Ldlr deficiency, Hmgcrm−/m− mice developed significantly smaller atherosclerotic lesions than Hmgcrfl/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 Hmgcrm−/m− macrophages to the lesions was reduced compared with Hmgcrfl/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.