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Myeloid TM6SF2 Deficiency Inhibits Atherosclerosis

Wenzhen Zhu1, Wenying Liang1, Haocheng Lu1,2

  • 1Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA.

Cells
|September 23, 2022
PubMed

Insights

Myeloid transmembrane 6 superfamily member 2 (TM6SF2) deficiency inhibits atherosclerosis development by reducing inflammation and foam cell formation. This finding highlights TM6SF2 as a potential therapeutic target for treating atherogenesis.

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Immunology

Background:

  • Genetic variants in TM6SF2 are linked to atherosclerotic cardiovascular disease (ASCVD).
  • Atherosclerosis pathogenesis involves chronic inflammation and macrophage foam cell formation.

Purpose of the Study:

  • To investigate the biological function of TM6SF2 in macrophages.
  • To determine TM6SF2's role in atherosclerosis development.

Main Methods:

  • Generated myeloid cell-specific Tm6sf2 knockout mice on an ApoE-deficient background.
  • Fed mice a Western diet to induce atherosclerosis and analyzed plaque formation.
  • Utilized RNA sequencing on bone marrow-derived macrophages (BMDMs) and THP-1 derived macrophages.

Main Results:

  • Myeloid Tm6sf2 deficiency inhibited atherosclerosis and reduced plaque foam cells without altering plasma lipids.
  • Gene expression analysis showed downregulated inflammation, cholesterol uptake, and ER stress genes in knockout macrophages.
  • TM6SF2 upregulation by oxLDL and its role in promoting inflammation, ER stress, and foam cell formation were confirmed.

Conclusions:

  • Myeloid TM6SF2 deficiency attenuates atherosclerosis development.
  • TM6SF2 plays a critical role in macrophage-driven atherogenesis.
  • Targeting myeloid TM6SF2 presents a potential therapeutic strategy for treating atherosclerosis.
Keywords:
ER stressTM6SF2atherosclerosischolesterolinflammationmacrophage

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