A novel MyD88 inhibitor LM9 prevents atherosclerosis by regulating inflammatory responses and oxidative stress in macrophages

Toxicol Appl Pharmacol. 2019 May 1:370:44-55. doi: 10.1016/j.taap.2019.03.012. Epub 2019 Mar 14.

Abstract

Development of atherosclerosis involves chronic and sustained inflammation and oxidative stress. Recent studies have linked atherosclerosis to the innate immune system. Genetic deficiency in myeloid differentiation primary-response protein 88 (MyD88) protects against the development and progression of atherosclerosis. However, it is unknown if pharmacological inhibition of MyD88 is able to be a therapeutic strategy for this disease. In this study, we evaluated the effect of a newly synthesized small-molecule inhibitor of MyD88, LM9, in an ApoE-/- mouse model of atherosclerosis. Our results showed that the major source of MyD88 in atherosclerotic lesions is infiltrated macrophage. Treatment of HFD-fed ApoE-/- mice with LM9 significantly attenuated the pathogenesis of atherosclerosis, accompanied with reduced vascular inflammatory responses and oxidative stress. These effects were achieved without changes to serum lipid levels. We further showed that LM9 inhibited oxidized-lipoprotein induced foam cell formation through suppression of MyD88 and inflammatory pathway in macrophages. Additionally, either LM9 treatment or MyD88 knockdown prevented ox-LDL-induced oxidative stress in macrophages. This study highlights the translational role of MyD88 as a therapeutic target and identifies the MyD88 inhibitor LM9 as a new candidate for the treatment of atherosclerosis.

Keywords: Atherosclerosis; Inflammation; Macrophage; MyD88; Oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Atherosclerosis / etiology
  • Atherosclerosis / prevention & control*
  • Diet, High-Fat
  • Disease Models, Animal
  • Gene Knockdown Techniques
  • Lipoproteins, LDL / metabolism
  • Lipoproteins, LDL / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / antagonists & inhibitors*
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism
  • Oxidative Stress / drug effects
  • Piperazines / pharmacology*
  • RAW 264.7 Cells
  • Reactive Oxygen Species / metabolism
  • Thiazoles / pharmacology*

Substances

  • Apolipoproteins E
  • Lipoproteins, LDL
  • MyD88 inhibitor LM9
  • Myeloid Differentiation Factor 88
  • Piperazines
  • Reactive Oxygen Species
  • Thiazoles
  • oxidized low density lipoprotein