4.6 Article

Myeloid TM6SF2 Deficiency Inhibits Atherosclerosis

期刊

CELLS
卷 11, 期 18, 页码 -

出版社

MDPI
DOI: 10.3390/cells11182877

关键词

TM6SF2; macrophage; cholesterol; atherosclerosis; ER stress; inflammation

资金

  1. National Institutes of Health [HL137214, HL134569, HL159871, HL138139, HL151524]

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Genetic variants in TM6SF2 are associated with atherosclerosis, and myeloid TM6SF2 deficiency inhibits atherosclerosis development and foam cell formation by reducing inflammation and ER stress.
Genetic variants in transmembrane 6 superfamily member 2 (TM6SF2), such as E167K, are associated with atherosclerotic cardiovascular disease (ASCVD). Chronic inflammation and lipid-laden macrophage foam cell formation are the central pathogeneses in the development of atherosclerosis. This study was undertaken to illustrate the biological function of TM6SF2 in macrophages and its role during atherosclerosis development. We generated myeloid cell-specific Tm6sf2 knockout mice on ApoE-deficient background (LysM Cre+/Tm6sf2(fl/fl)/ApoE(-/-), TM6 mKO) with littermate LysM Cre-/Tm6sf2(fl/fl)/ApoE(-/-) (Control) mice as controls. Mice were fed a Western diet for 12 weeks to induce atherosclerosis. Myeloid Tm6sf2 deficiency inhibited atherosclerosis and decreased foam cells in the plaques without changing the plasma lipid profile. RNA sequencing of bone marrow-derived macrophages (BMDMs) from TM6 mKO mice demonstrated the downregulation of genes associated with inflammation, cholesterol uptake, and endoplasmic reticulum (ER) stress. TM6SF2 was upregulated by oxidized low-density lipoprotein (oxLDL) in macrophages. Silencing TM6SF2 in THP-1-derived macrophages and Tm6sf2 deficiency in BMDMs reduced inflammatory responses and ER stress and attenuated cholesterol uptake and foam cell formation, while the overexpression of TM6SF2 showed opposite effects. In conclusion, myeloid TM6SF2 deficiency inhibits atherosclerosis development and is a potential therapeutic target for the treatment of atherogenesis.

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