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 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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