microRNA-155 Is Decreased During Atherosclerosis Regression and Is Increased in Urinary Extracellular Vesicles During Atherosclerosis Progression.
microRNA-155 Is Decreased During Atherosclerosis Regression and Is Increased in Urinary Extracellular Vesicles During Atherosclerosis Progression.
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DOI：
10.3389/fimmu.2020.576516
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发表时间：
2020
影响因子：
7.3
通讯作者：
Belton O
中科院分区：
文献类型：
--
作者：
Fitzsimons S;Oggero S;Bruen R;McCarthy C;Strowitzki MJ;Mahon NG;Ryan N;Brennan EP;Barry M;Perretti M;Belton O
动脉粥样硬化是一种由巨噬细胞聚集在中、大动脉中引起的慢性炎症性疾病。巨噬细胞极化和炎症是由调节炎症蛋白表达和胆固醇运输的microrna （miR）控制的。先前的转录组学分析使我们假设miR-155-5p （miR-155）受共轭亚油酸（CLA）的调节，CLA是一种促进体内动脉粥样硬化消退的介质。同时，由于细胞外囊泡（EVs）及其miR含量具有作为生物标志物的潜力，我们研究了人类冠状动脉疾病（CAD）进展过程中尿源性EVs （uEVs）的变化。我们在ApoE−/−小鼠的主动脉中量化miR-155的表达，这些小鼠被喂食1%的胆固醇饮食，并添加了CLA混合物（分别为80:20，顺式-9，反式-11：反式-10，顺式-12），这些混合物已被证明可以诱导动脉粥样硬化消退。同时，我们利用人极化THP-1巨噬细胞来研究CLA混合物对miR-155表达的影响。使用miR-155模拟物来研究其对巨噬细胞和离体人颈动脉内膜切除术（CEA）斑块标本的炎症作用（n = 5）。分析诊断为不稳定型（n = 12）和稳定型（n = 12） CAD患者的尿细胞外囊泡（uEVs）中表面标志物的表达和miR含量。在这里，我们报道了1%的胆固醇饮食增加了miR-155的表达，而CLA混合物在体内动脉粥样硬化消退过程中降低了miR-155的表达。CLA混合物也降低了体外人THP-1极化巨噬细胞中miR-155的表达。此外，在THP-1巨噬细胞中，miR-155模拟物降低了抗炎信号蛋白BCL-6和磷酸化stat -3。此外，miR-155在CEA斑块标本中模拟下调的BCL-6。与稳定CAD患者相比，不稳定CAD患者的uev中miR-155的表达增加。在不稳定CAD患者中，虽然uev的总浓度降低，但CD45+ uev水平升高。此外，不稳定CAD患者CD11b+ uEVs升高，CD16+ uEVs降低。miR-155抑制巨噬细胞中的抗炎信号，在体内动脉粥样硬化消退期间降低，在不稳定CAD患者的uEVs中升高，这表明miR-155具有作为预后指标和治疗靶点的潜力。
Atherosclerosis is a chronic inflammatory disease driven by macrophage accumulation in medium and large sized arteries. Macrophage polarization and inflammation are governed by microRNAs (miR) that regulate the expression of inflammatory proteins and cholesterol trafficking. Previous transcriptomic analysis led us to hypothesize that miR-155-5p (miR-155) is regulated by conjugated linoleic acid (CLA), a pro-resolving mediator which induces regression of atherosclerosis in vivo. In parallel, as extracellular vesicles (EVs) and their miR content have potential as biomarkers, we investigated alterations in urinary-derived EVs (uEVs) during the progression of human coronary artery disease (CAD). miR-155 expression was quantified in aortae from ApoE−/− mice fed a 1% cholesterol diet supplemented with CLA blend (80:20, cis-9,trans-11:trans-10,cis-12 respectively) which had been previously been shown to induce atherosclerosis regression. In parallel, human polarized THP-1 macrophages were used to investigate the effects of CLA blend on miR-155 expression. A miR-155 mimic was used to investigate its inflammatory effects on macrophages and on ex vivo human carotid endarterectomy (CEA) plaque specimens (n = 5). Surface marker expression and miR content were analyzed in urinary extracellular vesicles (uEVs) obtained from patients diagnosed with unstable (n = 12) and stable (n = 12) CAD. Here, we report that the 1% cholesterol diet increased miR-155 expression while CLA blend supplementation decreased miR-155 expression in the aorta during atherosclerosis regression in vivo. CLA blend also decreased miR-155 expression in vitro in human THP-1 polarized macrophages. Furthermore, in THP-1 macrophages, miR-155 mimic decreased the anti-inflammatory signaling proteins, BCL-6 and phosphorylated-STAT-3. In addition, miR-155 mimic downregulated BCL-6 in CEA plaque specimens. uEVs from patients with unstable CAD had increased expression of miR-155 in comparison to patients with stable CAD. While the overall concentration of uEVs was decreased in patients with unstable CAD, levels of CD45+ uEVs were increased. Additionally, patients with unstable CAD had increased CD11b+ uEVs and decreased CD16+ uEVs. miR-155 suppresses anti-inflammatory signaling in macrophages, is decreased during regression of atherosclerosis in vivo and is increased in uEVs from patients with unstable CAD suggesting miR-155 has potential as a prognostic indicator and a therapeutic target.
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影响因子：
3.7
作者：
Barutta F;Tricarico M;Corbelli A;Annaratone L;Pinach S;Grimaldi S;Bruno G;Cimino D;Taverna D;Deregibus MC;Rastaldi MP;Perin PC;Gruden G
通讯作者：
Gruden G
影响因子：
6
作者：
Ghai V;Wu X;Bheda-Malge A;Argyropoulos CP;Bernardo JF;Orchard T;Galas D;Wang K
通讯作者：
Wang K
影响因子：
--
作者：
Guo, Jing;Liu, Hui-Bin;Du, Zhi-Min
通讯作者：
Du, Zhi-Min
影响因子：
5.1
作者：
de Gaetano, Monica;Alghamdi, Kawthar;Belton, Orina
通讯作者：
Belton, Orina
影响因子：
16
作者：
Kalani, M. Yashar S.;Alsop, Eric;Van Keuren-Jensen, Kendall
通讯作者：
Van Keuren-Jensen, Kendall