| First Author | Sakai K | Year | 2018 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 38 |
| Issue | 11 | Pages | 2590-2600 |
| PubMed ID | 30354246 | Mgi Jnum | J:285130 |
| Mgi Id | MGI:6385437 | Doi | 10.1161/ATVBAHA.118.311664 |
| Citation | Sakai K, et al. (2018) Myeloid HMG-CoA (3-Hydroxy-3-Methylglutaryl-Coenzyme A) Reductase Determines Atherosclerosis by Modulating Migration of Macrophages. Arterioscler Thromb Vasc Biol 38(11):2590-2600 |
| abstractText | 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. |
