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

Kent Sakai1, Shuichi Nagashima1, Tetsuji Wakabayashi1

  • 1From 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.

Arteriosclerosis, Thrombosis, and Vascular Biology
|October 26, 2018
PubMed

Insights

Reducing 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in myeloid cells curtails atherosclerosis development. This occurs by decreasing immune cell migration to lesions, suggesting a novel therapeutic target for cardiovascular disease.

Area of Science:

  • Cardiovascular Biology
  • Immunology
  • Metabolic Disease

Background:

  • 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibition lowers LDL cholesterol and is atheroprotective.
  • The specific role of HMGCR within myeloid cells in atherosclerosis remains unclear.

Purpose of the Study:

  • To investigate the contribution of myeloid cell HMGCR to atherosclerosis development.
  • To determine if reducing HMGCR in myeloid cells impacts macrophage function and lesion progression.

Main Methods:

  • Generated mice with genetically reduced HMGCR in myeloid cells (Hmgcrm-/m-) using LysM-Cre.
  • Compared macrophage function in vitro and atherosclerosis extent in vivo (in Ldlr-deficient mice) between Hmgcrm-/m- and control (Hmgcrfl/fl) mice.

Main Results:

  • Hmgcrm-/m- myeloid cells exhibited reduced HMGCR expression, cholesterol biosynthesis, migration, proliferation, and survival.
  • Hmgcrm-/m- mice had significantly smaller atherosclerotic lesions compared to controls in the absence of LDL receptors.
  • Reduced in vivo migration of Hmgcrm-/m- macrophages to atherosclerotic lesions was observed.

Conclusions:

  • Genetic reduction of HMGCR in myeloid cells confers atheroprotection.
  • This protection is primarily mediated by decreased monocyte/macrophage migration to atherosclerotic lesions.
  • Targeting myeloid HMGCR represents a potential therapeutic strategy for atherosclerosis.

Keywords:
LDL receptoratherosclerosischolesterolmacrophagesmicemonocytessmall GTPase proteins

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