Protective Functions of Liver X Receptor α in Established Vulnerable Plaques: Involvement of Regulating Endoplasmic Reticulum-Mediated Macrophage Apoptosis and Efferocytosis.
Protective Functions of Liver X Receptor α in Established Vulnerable Plaques: Involvement of Regulating Endoplasmic Reticulum-Mediated Macrophage Apoptosis and Efferocytosis.
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肝脏 X 受体 α 在已形成的易损斑块中的保护功能：参与调节内质网介导的巨噬细胞凋亡和胞吞作用
DOI：
10.1161/jaha.120.018455
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发表时间：
2021-05-18
影响因子：
5.4
通讯作者：
Pu J
中科院分区：
文献类型：
--
作者：
Che X;Xiao Q;Song W;Zhang H;Sun B;Geng N;Tao Z;Shao Q;Pu J
肝脏X受体（LXR）属于代谢核受体超家族，在血管生理/病理学中发挥着关键的调节作用。然而，全身 LXR 激活对已建立的易损斑块的影响以及所涉及的潜在同种型特异性作用仍不清楚。 8周大的雄性载脂蛋白E−/−小鼠接受颈动脉分支结扎和肾动脉收缩，并结合高脂肪饮食。 4 周后，左颈动脉的斑块获得了脆弱的特征，经磁共振成像扫描和组织学分析证实。从那时起，小鼠每天腹腔注射 PBS 或 GW3965（每天 10 毫克/千克），持续 4 周。与载体组相比，LXR 激动剂治疗使病变体积减少了 52.61%。更重要的是，发现斑块内出血较少且坏死核心形成较少。这些措施共同降低了斑块破裂的发生率。从机制上讲，该过程涉及减少病变细胞凋亡、增强胞吞作用和减轻内质网应激。此外，LXRα（而非 LXRβ）的基因消融削弱了 LXR 对腹膜巨噬细胞中内质网应激诱导的 C/EBP 同源蛋白通路的保护作用。与 LXRα 在体外的主导作用相一致，激活的 LXR 未能稳定 LXRα−/− 载脂蛋白 E−/− 小鼠中的易损斑块并纠正获得性细胞异常。我们的结果表明，LXRα 介导 LXR 激活的能力，通过改善巨噬细胞内质网应激、病变细胞凋亡和胞吞作用缺陷来稳定易损斑块并防止斑块破裂。这些发现可能会扩大 LXR 治疗动脉粥样硬化的应用场景。
Liver X receptor (LXR) belongs to the metabolic nuclear receptor superfamily, which plays a critical regulatory role in vascular physiology/pathology. However, effects of systemic LXR activation on established vulnerable plaques and the potential isotype‐specific role involved remain unclear. The 8‐week‐old male apolipoprotein E−/− mice went through carotid branch ligation and renal artery constriction, combined with a high‐fat diet. Plaques in the left carotid artery acquired vulnerable features 4 weeks later, confirmed by magnetic resonance imaging scans and histological analysis. From that time on, mice were injected intraperitoneally daily with PBS or GW3965 (10 mg/kg per day) for an additional 4 weeks. Treatment with LXR agonists reduced the lesion volume by 52.61%, compared with the vehicle group. More important, a profile of less intraplaque hemorrhage detection and necrotic core formation was found. These actions collectively attenuated the incidence of plaque rupture. Mechanistically, reduced lesional apoptosis, enhanced efferocytosis, and alleviated endoplasmic reticulum stress are involved in the process. Furthermore, genetic ablation of LXRα, but not LXRβ, blunted the protective effects of LXR on the endoplasmic reticulum stress–elicited C/EBP‐homologous protein pathway in peritoneal macrophages. In concert with the LXRα‐predominant role in vitro, activated LXR failed to stabilize vulnerable plaques and correct the acquired cellular anomalies in LXRα−/− apolipoprotein E−/− mice. Our results revealed that LXRα mediates the capacity of LXR activation to stabilize vulnerable plaques and prevent plaque rupture via amelioration of macrophage endoplasmic reticulum stress, lesional apoptosis, and defective efferocytosis. These findings might expand the application scenarios of LXR therapeutics for atherosclerosis.