Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University, Frankfurt, Germany (S.C., K.M.M., A.F., L.P., N.J., R.A.B., M.M.-R., D.J., S.U., S.D.).
Department of Cardiology, Internal Medicine III, Johann Wolfgang Goethe-University Hospital, Frankfurt, Germany (S.C., A.Z.).
Circulation. 2019 Mar 5;139(10):1320-1334. doi: 10.1161/CIRCULATIONAHA.117.029015.
The majority of the human genome comprises noncoding sequences, which are in part transcribed as long noncoding RNAs (lncRNAs). lncRNAs exhibit multiple functions, including the epigenetic control of gene expression. In this study, the effect of the lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) on atherosclerosis was examined.
The effect of MALAT1 on atherosclerosis was determined in apolipoprotein E-deficient (Apoe) MALAT1-deficient (Malat1) mice that were fed with a high-fat diet and by studying the regulation of MALAT1 in human plaques.
Apoe Malat1 mice that were fed a high-fat diet showed increased plaque size and infiltration of inflammatory CD45 cells compared with Apoe Malat1 control mice. Bone marrow transplantation of Apoe Malat1 bone marrow cells in Apoe Malat1 mice enhanced atherosclerotic lesion formation, which suggests that hematopoietic cells mediate the proatherosclerotic phenotype. Indeed, bone marrow cells isolated from Malat1 mice showed increased adhesion to endothelial cells and elevated levels of proinflammatory mediators. Moreover, myeloid cells of Malat1 mice displayed enhanced adhesion to atherosclerotic arteries in vivo. The anti-inflammatory effects of MALAT1 were attributed in part to reduction of the microRNA miR-503. MALAT1 expression was further significantly decreased in human plaques compared with normal arteries and was lower in symptomatic versus asymptomatic patients. Lower levels of MALAT1 in human plaques were associated with a worse prognosis.
Reduced levels of MALAT1 augment atherosclerotic lesion formation in mice and are associated with human atherosclerotic disease. The proatherosclerotic effects observed in Malat1 mice were mainly caused by enhanced accumulation of hematopoietic cells.
人类基因组的大部分由非编码序列组成，其中一部分转录为长非编码 RNA（lncRNA）。lncRNA 具有多种功能，包括基因表达的表观遗传调控。在本研究中，研究了 lncRNA MALAT1（转移相关肺腺癌转录本 1）对动脉粥样硬化的影响。
通过在高脂饮食喂养的载脂蛋白 E 缺陷（Apoe）MALAT1 缺陷（Malat1）小鼠中以及研究 MALAT1 在人斑块中的调节作用来确定 MALAT1 对动脉粥样硬化的影响。
与 Apoe Malat1 对照小鼠相比，高脂饮食喂养的 Apoe Malat1 小鼠的斑块大小增加，炎症性 CD45 细胞浸润增加。将 Apoe Malat1 骨髓细胞移植到 Apoe Malat1 小鼠中增强了动脉粥样硬化病变的形成，这表明造血细胞介导了动脉粥样硬化前表型。事实上，从 Malat1 小鼠中分离出的骨髓细胞显示出与内皮细胞的粘附增加和促炎介质水平升高。此外，Malat1 小鼠的髓样细胞在体内显示出对动脉粥样硬化动脉的粘附增强。MALAT1 的抗炎作用部分归因于微 RNA miR-503 的减少。与正常动脉相比，MALAT1 在人斑块中的表达明显降低，并且在有症状与无症状患者中，MALAT1 的表达水平更低。人斑块中 MALAT1 水平降低与预后较差相关。
MALAT1 水平降低可增强小鼠动脉粥样硬化病变的形成，并与人动脉粥样硬化疾病相关。在 Malat1 小鼠中观察到的动脉粥样硬化前效应主要是由于造血细胞的积累增强所致。
