Introduction Genome Wide Association Studies have identified Tribbles-1 (TRIB1) as a regulator of plasma lipid levels and a risk factor for MI. Studies using Trib1 full body- and liver specific knockout mice have shown that hepatic expression of Trib1 reduces circulating lipids1. Additionally, Trib1 has been shown to be a regulator of alternatively activated macrophage polarisation2. However, there has been no study to directly evaluate the role of myeloid Trib1 (mTrib1) in atherogenesis.
Methods To determine the role of mTrib1 in atherosclerosis, we developed myeloid-Trib1 deficient (mTrib1KO) and overexpression (mTrib1Tg) mouse strains. To distinguish between metabolic and inflammatory drivers of atherosclerosis, bone marrow from these strains were transplanted into lethally irradiated ApoE-/- mice and fed on a western diet for 12 weeks. Additionally, we also induced atherosclerosis in mTrib1Tg and mTrib1WT strains by injecting rAAV8/mPCSK9 and fed western diet for 12 weeks.
Results mTrib1KO→ApoE-/- mice were protected while mTrib1Tg→ApoE-/- mice presented with increased atherosclerotic burden in both the aorta (p<0.05) and aortic sinus (p<0.05) with significantly increased number of foam cell macrophages. Additionally, in vitro studies showed that BMDMs from mTrib1Tg mice uptake more oxidised LDL (oxLDL) and have dyrsegulated levels of the oxLDL scavenger receptor (OLR1) and lipid handling gene expression. Initial analysis from our rAAV8/mPCSK9 study supports our findings with mTrib1Tg-PCSK9 mice exhibiting a higher burden of atherosclerosis in the aorta (p<0.05).
Conclusion We conclude that Trib1 is a potent regulator of atherosclerosis, the over-expression of which promotes atherogenesis through elevated oxLDL uptake and subsequent foam cell formation in plaque macrophages.
. Burkhardt et al. JCI (2010);120:4410–4414.
. Satoh et al. Nature (2013);7442:524–8.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.