MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1.
MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1.
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动脉粥样硬化是一种高脂血症引起的动脉壁慢性炎症过程，优先发生在层流紊乱损害内皮细胞（EC）功能的部位。在这里，我们发现内皮miR-126-5p通过抑制Notch1抑制剂delta-like 1同源物（Dlk1）在内皮细胞中维持增殖储备，从而防止动脉粥样硬化病变形成。在Mir126−/−小鼠中，由于缺乏miR-126-5p而非miR-126-3p通过抑制Dlk1而降低EC增殖，因此剥落后内皮恢复受损。在非偏好位点，内皮细胞中的高miR-126-5p水平赋予了增殖储备，补偿了高脂血症的抗增殖作用，因此mir -126−/−小鼠的动脉粥样硬化加剧。相比之下，通过血流紊乱下调miR-126-5p，通过上调Dlk1表达，可消除高脂血症应激下易感部位的EC增殖。给药miR-126-5p可挽救EC在偏爱部位的增殖和有限的动脉粥样硬化，引入一种潜在的治疗方法。
Atherosclerosis, a hyperlipidemia-induced chronic inflammatory process of the arterial wall, develops preferentially at sites where disturbed laminar flow compromises endothelial cell (EC) function. Here we show that endothelial miR-126-5p maintains a proliferative reserve in ECs through suppression of the Notch1 inhibitor delta-like 1 homolog (Dlk1) and thereby prevents atherosclerotic lesion formation. Endothelial recovery after denudation was impaired in Mir126−/− mice because lack of miR-126-5p, but not miR-126-3p, reduced EC proliferation by derepressing Dlk1. At nonpredilection sites, high miR-126-5p levels in endothelial cells confer a proliferative reserve that compensates for the antiproliferative effects of hyperlipidemia, such that atherosclerosis was exacerbated in Mir126−/− mice. In contrast, downregulation of miR-126-5p by disturbed flow abrogated EC proliferation at predilection sites in response to hyperlipidemic stress through upregulation of Dlk1 expression. Administration of miR-126-5p rescued EC proliferation at predilection sites and limited atherosclerosis, introducing a potential therapeutic approach.
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DOI：
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发表时间：
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