The atheroprotective role of lipoxin A4 prevents oxLDL-induced apoptotic signaling in macrophages via JNK pathway

Atherosclerosis. 2018 Nov:278:259-268. doi: 10.1016/j.atherosclerosis.2018.09.025. Epub 2018 Sep 28.

Abstract

Background and aims: We examined whether the inflammation resolution mediator lipoxin A4 (LXA4) inhibits foam cell formation and oxidized low-density lipoprotein (oxLDL)-induced apoptotic signaling in macrophages and the role of circulating/local LXA4 biosynthesis in atherogenesis.

Methods: LXA4 levels were measured by enzyme-linked immunosorbent assay. Dil-oxLDL and Dil-acLDL binding to and uptake by macrophages were evaluated by flow cytometry. Apoptosis was evaluated by TUNEL and Annexin V/PI assays.

Results: Circulating LXA4 levels in patients with coronary artery disease were much higher than those in respective controls. Local LXA4 levels were much lower in rabbit atherosclerotic vessel walls. Interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) were elevated in atherosclerotic vessels. After the inflammatory stimulus (IFN-γ, TNF-α, and C-reactive protein), LXA4 synthesis decreased significantly in foam cells. LXA4 dose-dependently suppressed the expression of the cholesterol uptake genes CD36 and SR-A in macrophages, which was blocked by the LXA4 receptor antagonist BOC-2. LXA4 also inhibited oxLDL-induced CD36 upregulation, Dil-oxLDL uptake, and foam cell formation. Furthermore, LXA4 inhibited the oxLDL-activated c-Jun N-terminal kinase pathway and reduced oxLDL-induced macrophage apoptosis by inhibiting caspase-3 activation and restoring the mitochondrial membrane potential.

Conclusions: We found that LXA4 inhibited foam cell formation, oxLDL-induced inflammation, and apoptotic signaling in macrophages. Insufficient levels of the anti-inflammatory pro-resolution molecule LXA4 were found in rabbit atherosclerotic arteries, which might contribute to preventing inflammation resolution during atherogenesis.

Keywords: Apoptosis; Atherosclerosis; Lipid uptake; Lipoxin A(4); Macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • CD36 Antigens / metabolism
  • Coronary Artery Disease / metabolism*
  • Foam Cells / metabolism
  • Humans
  • Hydroxyeicosatetraenoic Acids
  • Inflammation
  • Lipoproteins, LDL / metabolism*
  • Lipoxins / blood*
  • Lipoxins / physiology
  • MAP Kinase Kinase 4 / metabolism*
  • MAP Kinase Signaling System / drug effects
  • Macrophages / metabolism*
  • Male
  • Rabbits
  • Scavenger Receptors, Class A / metabolism
  • THP-1 Cells

Substances

  • CD36 Antigens
  • Hydroxyeicosatetraenoic Acids
  • Lipoproteins, LDL
  • Lipoxins
  • Scavenger Receptors, Class A
  • lipoxin A4
  • oxidized low density lipoprotein
  • 15-hydroxy-5,8,11,13-eicosatetraenoic acid
  • MAP Kinase Kinase 4