SREBF1/MicroRNA-33b Axis Exhibits Potent Effect on Unstable Atherosclerotic Plaque Formation In Vivo

Arterioscler Thromb Vasc Biol. 2018 Oct;38(10):2460-2473. doi: 10.1161/ATVBAHA.118.311409.

Abstract

Objective- Atherosclerosis is a common disease caused by a variety of metabolic and inflammatory disturbances. MicroRNA (miR)-33a within SREBF2 (sterol regulatory element-binding factor 2) is a potent target for treatment of atherosclerosis through regulating both aspects; however, the involvement of miR-33b within SREBF1 remains largely unknown. Although their host genes difference could lead to functional divergence of miR-33a/b, we cannot dissect the roles of miR-33a/b in vivo because of lack of miR-33b sequences in mice, unlike human. Approach and Results- Here, we analyzed the development of atherosclerosis using miR-33b knock-in humanized mice under apolipoprotein E-deficient background. MiR-33b is prominent both in human and mice on atheroprone condition. MiR-33b reduced serum high-density lipoprotein cholesterol levels and systemic reverse cholesterol transport. MiR-33b knock-in macrophages showed less cholesterol efflux capacity and higher inflammatory state via regulating lipid rafts. Thus, miR-33b promotes vulnerable atherosclerotic plaque formation. Furthermore, bone marrow transplantation experiments strengthen proatherogenic roles of macrophage miR-33b. Conclusions- Our data demonstrated critical roles of SREBF1-miR-33b axis on both lipid profiles and macrophage phenotype remodeling and indicate that miR-33b is a promising target for treating atherosclerosis.

Keywords: atherosclerosis; bone marrow transplantation; cholesterol, HDL; lipid metabolism; microRNAs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Apoptosis
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • Bone Marrow Transplantation
  • Case-Control Studies
  • Cholesterol, HDL / blood
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation
  • Humans
  • Intestinal Absorption
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Membrane Microdomains / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout, ApoE
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Middle Aged
  • Phenotype
  • Plaque, Atherosclerotic*
  • Signal Transduction
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism*
  • Triglycerides / blood

Substances

  • Cholesterol, HDL
  • MIRN33a microRNA, human
  • MicroRNAs
  • SREBF1 protein, human
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Triglycerides