TRPA1 regulates macrophages phenotype plasticity and atherosclerosis progression

Atherosclerosis. 2020 May:301:44-53. doi: 10.1016/j.atherosclerosis.2020.04.004. Epub 2020 Apr 13.

Abstract

Background and aims: TRPA1 is a calcium permeable non-selective cation channel, its expression is up-regulated in atherosclerosis plaque, yet its function in macrophages activation is unknown. We sought to establish the role of TRPA1 in inflammatory macrophages activation.

Methods: TRPA1-/-ApoE-/- mice and C57BL/6 J control were treated with a high-fat diet (HFD) and the TRPA1 agonist cinnamaldehyde (CIN). Third-order branches of superior aorta of patients and mice were collected. Oil Red O staining and hematoxylin and eosin staining were performed to measure atherosclerotic lesions. The RNA-seq was performed to identify TRPA1 function in atherosclerosis. The expression of bone marrow-derived macrophages (BMDMs) markers was tested by Western blot. In addition, the levels of inflammatory factors were checked by ELISA. Chromatin immunoprecipitation (ChIP)-PCR and luciferase reporter gene assays were used to explore if TRPA1 could regulate histone modifications.

Results: TRPA1-/-ApoE-/- mice showed a significant increase in atherosclerosis plaques compared to ApoE-/- mice after HFD treatment. Conversely, activation of TRPA1 by CIN sharply reduced atherosclerosis progression. Atherosclerosis was associated with a significant change in macrophage polarization toward the M1 proinflammatory phenotype. We found that inhibition of TRPA1 remarkably stimulated M1 marker genes expression, while repressed M2 marker genes expression. The interaction between TRPA1 and Ezh2, a subunit of polycomb repressive complex 2, suppressed the proteasome-dependent degradation of Ezh2. Thus, TRPA1 epigenetically regulated H3K27 trimethylation level in macrophages.

Conclusions: Our results demonstrate that TRPA1, up-regulated in atherosclerosis plaque, could regulate the macrophages toward an inflammatory phenotype, thereby modulating atherosclerosis progression. Activation of TRPA1 might serve as an atherosclerosis therapeutic target.

Keywords: Atherosclerosis; Inflammation; Macrophages; TRPA1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / genetics
  • Atherosclerosis* / genetics
  • Disease Models, Animal
  • Humans
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • Plaque, Atherosclerotic*
  • TRPA1 Cation Channel / genetics

Substances

  • Apolipoproteins E
  • TRPA1 Cation Channel
  • TRPA1 protein, human
  • Trpa1 protein, mouse