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

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 reducedHmgcr in myeloid cells (Hmgcr m− /m − ) using LysM (Cre) and compared various functions of their macrophages to those ofHmgcr fl/fl control mice. We further compared the extent of atherosclerosis inHmgcr m −/m −andHmgcr fl/fl mice in the absence ofLdlr (LDL receptor).Hmgcr m −/m −macrophages and granulocytes had significantly lowerHmgcr mRNA expression and cholesterol biosynthesis thanHmgcr fl/fl cells. In vitro,Hmgcr m −/m −monocytes/macrophages had reduced ability to migrate, proliferate, and survive compared withHmgcr 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 inHmgcr m −/m −macrophages. In the setting ofLdlr deficiency,Hmgcr m −/m −mice developed significantly smaller atherosclerotic lesions thanHmgcr 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 ofHmgcr m −/m −macrophages to the lesions was reduced compared withHmgcr 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.