PDF(Pubmed)
Abstract：
Tribbles 3 (TRIB3) modulates lipid and glucose metabolism, macrophage lipid uptake, with a gain-of-function variant associated with increased cardiovascular risk. Here we set out to examine the role of this pseudokinase in atherosclerotic plaque development. Human endarterectomy atherosclerotic tissue specimens analysed by immunofluorescence showed upregulated TRIB3 in unstable plaques and an enrichment in unstable regions of stable plaques. Atherosclerosis was induced in full body Trib3KO and Trib3WT littermate mice by injecting mPCSK9 expressing adeno-associated virus and western diet feeding for 12 weeks. Trib3KO mice showed expanded visceral adipose depot while circulatory lipid levels remained unaltered compared to wildtype mice. Trib3KO mice aortae showed a reduced plaque development and improved plaque stability, with increased fibrous cap thickness and collagen content, which was accompanied by increased macrophage content. Analysis of both mouse and human macrophages with reduced TRIB3 expression showed elongated morphology, increased actin expression and altered regulation of genes involved in extracellular matrix remodelling. In summary, TRIB3 controls plaque development and may be atherogenic in vivo. Loss of TRIB3 increases fibrous cap thickness via altered metalloproteinase expression in macrophages, thus inhibiting collagen and elastic fibre degradation, suggesting a role for TRIB3 in the formation of unstable plaques.
摘要：
Tribbles3（TRIB3）调节脂质和葡萄糖代谢，巨噬细胞脂质摄取，与心血管风险增加相关的功能获得变异。在这里，我们着手研究这种假激酶在动脉粥样硬化斑块发展中的作用。通过免疫荧光分析的人动脉内膜切除术动脉粥样硬化组织标本显示，不稳定斑块中的TRIB3上调，稳定斑块的不稳定区域富集。通过注射表达腺相关病毒的mPCSK9和西方饮食喂养12周，在全身Trib3KO和Trib3WT同窝小鼠中诱发动脉粥样硬化。与野生型小鼠相比，Trib3KO小鼠显示出扩大的内脏脂肪储库，而循环脂质水平保持不变。Trib3KO小鼠主动脉显示出减少的斑块发展和改善的斑块稳定性，随着纤维帽厚度和胶原蛋白含量的增加，伴随着巨噬细胞含量的增加。对TRIB3表达降低的小鼠和人巨噬细胞的分析显示出细长的形态，增加肌动蛋白表达和改变参与细胞外基质重塑的基因调节。总之,TRIB3控制斑块的发展并且在体内可能是致动脉粥样硬化的。TRIB3的缺失通过改变巨噬细胞中金属蛋白酶的表达增加纤维帽厚度，从而抑制胶原蛋白和弹性纤维的降解，提示TRIB3在不稳定斑块形成中的作用。
