Myeloid Tribbles 1 induces early atherosclerosis via enhanced foam cell expansion

Johnston, Jessica M. and Angyal, Adrienn and Bauer, Robert C and Hamby, Stephen and Suvarna, S Kim and Baidžajevas, Kajus and Hegedűs, Zoltán and Dear, T.Neil and Turner, Martin and Wilson, Heather L. and Goodall, Alison H. and Rader, Daniel J. and Shoulders, Carol C. and Francis, Sheila E. and Kiss-Tóth, Endre (2019) Myeloid Tribbles 1 induces early atherosclerosis via enhanced foam cell expansion. SCIENCE ADVANCES, 5 (10). ISSN 2375-2548

Preview

Text JohnstonSciAdv.pdf Download (2MB) | Preview

Abstract

Macrophages drive atherosclerotic plaque progression and rupture; hence, attenuating their atherosclerosis-inducing properties holds promise for reducing coronary heart disease (CHD). Recent studies in mouse models have demonstrated that Tribbles 1 (Trib1) regulates macrophage phenotype and shows that Trib1 deficiency increases plasma cholesterol and triglyceride levels, suggesting that reduced TRIB1 expression mediates the strong genetic association between the TRIB1 locus and increased CHD risk in man. However, we report here that myeloid-specific Trib1 (mTrib1) deficiency reduces early atheroma formation and that mTrib1 transgene expression increases atherogenesis. Mechanistically, mTrib1 increased macrophage lipid accumulation and the expression of a critical receptor (OLR1), promoting oxidized low-density lipoprotein uptake and the formation of lipid-laden foam cells. As TRIB1 and OLR1 RNA levels were also strongly correlated in human macrophages, we suggest that a conserved, TRIB1-mediated mechanism drives foam cell formation in atherosclerotic plaque and that inhibiting mTRIB1 could be used therapeutically to reduce CHD.

Actions (login required)

Edit Item