LncRNA NIPA1-SO confers atherosclerotic protection by suppressing the transmembrane protein NIPA1.
LncRNA NIPA1-SO confers atherosclerotic protection by suppressing the transmembrane protein NIPA1.
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DOI：
10.1016/j.jare.2023.01.017
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发表时间：
2023-12
影响因子：
10.7
通讯作者：
Hu, Yan-Wei
中科院分区：
文献类型：
--
作者：
Jiang, Min;Song, Yu;Ren, Mei-Xia;He, Run-Chao;Dong, Xian-Hui;Li, Xue-Heng;Lu, Zhi-Feng;Li, Shu;Wu, Jia;Bei, Yan-Rou;Liu, Fei;Long, Yan;Wu, Shao-Guo;Liu, Xue-Hui;Wu, Li-Mei;Yang, Hong-Ling;Mcvey, David G.;Dai, Xiao-Yan;Ye, Shu;Hu, Yan-Wei
NIPA 1-SO调控的信号通路示意图。我们的研究揭示了lncRNA NIPA 1-SO的动脉粥样硬化保护作用，其通过与单个转录因子相互作用，能够抑制单核细胞粘附和泡沫细胞形成，这是动脉粥样硬化的两个基本过程。转录因子FUBP 1负调控NIPA 1的表达;这种抑制作用通过NIPA 1-SO与FUBP 1的相互作用而增加，导致NIPA 1的转录降低。由于NIPA 1介导的BMPR 2内吞作用和降解减少，NIPA 1蛋白减少导致BMPR 2蛋白增加，导致更高水平的Smad 1/5/8磷酸化（pSmad 1/5/8），其通过与Smad 4复合，抑制粘附分子VCAM 1和ICAM 1的转录，减少单核细胞与内皮细胞的粘附。此外，pSmad 1/5/8：Smad 4复合物促进ABCA 1和ABCG 1的转录，这两者都促进胆固醇经由高密度脂蛋白（HDL）颗粒流出，从而抑制泡沫细胞形成。人动脉粥样硬化斑块中长链非编码RNA NIPA 1-SO的表达减少，NIPA 1的水平增加。NIPA 1-SO抑制单核细胞与内皮细胞的粘附并降低胆固醇积累。增加NIPAI-SO的表达或敲除NIPA 1减少动物模型中的动脉粥样硬化。长链非编码RNA（lncRNA）在基因调控和心血管疾病中发挥着重要作用。然而，lncRNA在动脉粥样硬化中的作用知之甚少。在本研究中，我们发现，在人类动脉粥样硬化斑块中，NIPA 1-SO的水平降低，而NIPA 1的水平升高。此外，NIPA 1-SO负调控人脐静脉内皮细胞（HUVECs）中NIPA 1的表达。机制上，NIPA 1-SO与转录因子FUBP 1和NIPA 1基因相互作用。NIPA 1-SO对NIPA 1蛋白水平的影响被FUBP 1的敲低逆转。NIPA 1-SO过表达增加，而NIPA 1-SO敲低降低BMPR 2水平;这些作用通过敲低NIPA 1而增强。NIPA 1-SO的过表达减少，而NIPA 1-SO敲低增加单核细胞粘附HUVECs;这些作用被BMPR 2敲低减弱。在低密度脂蛋白受体缺陷小鼠中，慢病毒介导的NIPA 1-SO过表达或基因靶向敲除NIPA 1可减少单核细胞-内皮细胞粘附和动脉粥样硬化病变形成。总的来说，这些发现揭示了lncRNA NIPA 1-SO的新的抗动脉粥样硬化作用，并强调了其通过结合FUBP 1并因此抑制NIPA 1表达对血管炎症和细胞内胆固醇积累的抑制作用。
Schematic diagram of the signalling pathways regulated by NIPA1-SO. Our study has uncovered an athero-protective role of the lncRNA NIPA1-SO, which, by interacting with a single transcription factor, is capable of inhibiting monocyte adhesion and foam cell formation, two fundamental processes in atherosclerosis. The transcription factor FUBP1 negatively regulates NIPA1 expression; this inhibitory effect is increased by the interaction of NIPA1-SO with FUBP1, resulting in lower transcription of NIPA1. A reduction in NIPA1 protein results in increased BMPR2 protein due to a reduction in NIPA1-mediated BMPR2 endocytosis and degradation, leading to higher levels of Smad1/5/8 phosphorylation (pSmad1/5/8), which, through complexation with Smad4, inhibit transcription of the adhesion molecules VCAM1 and ICAM1, reducing monocyte adhesion to endothelial cells. Further, the pSmad1/5/8:Smad4 complex promotes ABCA1 and ABCG1 transcription, both of which promote cholesterol efflux via high-density lipoprotein (HDL) particles, thereby inhibiting foam cell formation. Human atherosclerotic plaques have reduced expression of the long non-coding RNA NIPA1-SO and increased levels of NIPA1. NIPA1-SO inhibits monocyte adhesion to endothelial cells and decreases cholesterol accumulation. Increasing the expression of NIPAI-SO or knockout of NIPA1 reduces atherosclerosis in an animal model. Long non-coding RNAs (lncRNAs) are emerging as important players in gene regulation and cardiovascular diseases. However, the roles of lncRNAs in atherosclerosis are poorly understood. In the present study, we found that the levels of NIPA1-SO were decreased while those of NIPA1 were increased in human atherosclerotic plaques. Furthermore, NIPA1-SO negatively regulated NIPA1 expression in human umbilical vein endothelial cells (HUVECs). Mechanistically, NIPA1-SO interacted with the transcription factor FUBP1 and the NIPA1 gene. The effect of NIPA1-SO on NIPA1 protein levels was reversed by the knockdown of FUBP1. NIPA1-SO overexpression increased, whilst NIPA1-SO knockdown decreased BMPR2 levels; these effects were enhanced by the knockdown of NIPA1. The overexpression of NIPA1-SO reduced while NIPA1-SO knockdown increased monocyte adhesion to HUVECs; these effects were diminished by the knockdown of BMPR2. The lentivirus-mediated-overexpression of NIPA1-SO or gene-targeted knockout of NIPA1 in low-density lipoprotein receptor-deficient mice reduced monocyte-endothelium adhesion and atherosclerotic lesion formation. Collectively, these findings revealed a novel anti-atherosclerotic role for the lncRNA NIPA1-SO and highlighted its inhibitory effects on vascular inflammation and intracellular cholesterol accumulation by binding to FUBP1 and consequently repressing NIPA1 expression.
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影响因子：
20.1
作者：
Vacante F;Rodor J;Lalwani MK;Mahmoud AD;Bennett M;De Pace AL;Miller E;Van Kuijk K;de Bruijn J;Gijbels M;Williams TC;Clark MB;Scanlon JP;Doran AC;Montgomery R;Newby DE;Giacca M;O'Carroll D;Hadoke PWF;Denby L;Sluimer JC;Baker AH
通讯作者：
Baker AH
DOI：
10.1056/nejmoa072366
发表时间：
2007-08-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Samani NJ;Erdmann J;Hall AS;Hengstenberg C;Mangino M;Mayer B;Dixon RJ;Meitinger T;Braund P;Wichmann HE;Barrett JH;König IR;Stevens SE;Szymczak S;Tregouet DA;Iles MM;Pahlke F;Pollard H;Lieb W;Cambien F;Fischer M;Ouwehand W;Blankenberg S;Balmforth AJ;Baessler A;Ball SG;Strom TM;Braenne I;Gieger C;Deloukas P;Tobin MD;Ziegler A;Thompson JR;Schunkert H;WTCCC and the Cardiogenics Consortium
通讯作者：
WTCCC and the Cardiogenics Consortium
DOI：
10.17116/jnevro202112105175
发表时间：
2021-01-01
影响因子：
--
作者：
Rudenskaya, G E;Kadnikova, V A;Ryzhkova, O P
通讯作者：
Ryzhkova, O P
影响因子：
9.8
作者：
Rainier, S;Chai, JH;Fink, JK
通讯作者：
Fink, JK
影响因子：
1.9
作者：
Vanlerberghe, Clemence;Petit, Florence;Andrieux, Joris
通讯作者：
Andrieux, Joris