Macrophage LXRα gene therapy ameliorates atherosclerosis as well as hypertriglyceridemia in LDLR-/- mice
Macrophage LXRα gene therapy ameliorates atherosclerosis as well as hypertriglyceridemia in LDLR-/- mice
复制标题
DOI：
10.1038/gt.2011.29
复制
发表时间：
2011-08-01
期刊：
影响因子：
5.1
通讯作者：
Li, S.
中科院分区：
文献类型：
--
作者：
Li, G.;Biju, K. C.;Li, S.
肝脏X受体（LXRs）参与胆固醇稳态、炎症反应和动脉粥样硬化形成的调节。LXR激动剂的施用抑制动脉粥样硬化的进展，并且还增加血浆甘油三酯水平，这代表了它们用于治疗这种疾病的障碍。这项研究的目的是制定一种替代办法，可以克服这一障碍。用造血干细胞（HSC）富集的骨髓细胞移植八周龄低密度脂蛋白受体缺陷（LDLR-/-）小鼠，所述造血干细胞富集的骨髓细胞用表达由合成巨噬细胞启动子驱动的绿色荧光蛋白（GFP）（Lenti-SP-GFP，对照）或LXR α（Lenti-SP-LXR α）的慢病毒载体转导。在移植后4周，用西方饮食喂养小鼠8周，然后处死。与Lenti-SP-GFP小鼠相比，Lenti-SP-LXR α小鼠的动脉粥样硬化病变减少了30%，同时伴有胆固醇流出基因载脂蛋白E和ATP结合盒A1的巨噬细胞表达水平增加，以及血浆炎症细胞因子白细胞介素-6和肿瘤坏死因子-α的减少。有趣的是，还观察到血浆甘油三酯水平降低50%。我们的结论是，HSC为基础的巨噬细胞LXR α基因治疗改善动脉粥样硬化的发展沿着意想不到的降低血浆甘油三酯水平的LDLR-/-小鼠。这些发现强调了巨噬细胞LXR表达作为动脉粥样硬化治疗干预途径的潜在价值。Gene Therapy（2011）18，835-841; doi：10.1038/gt.2011.29; 2011年3月10日在线发表
Liver X receptors (LXRs) are implicated in the regulation of cholesterol homeostasis, inflammatory response and atherogenesis. Administration of LXR agonists inhibits the progress of atherosclerosis, and also increases plasma triglyceride levels, representing an obstacle to their use in treating this disease. The objective of this study was to develop an alternative approach that could overcome this obstacle. Eight-week-old low-density lipoprotein receptor-deficient (LDLR-/-)mice were transplanted with hematopoietic stem cell (HSC)-enriched bone marrow cells transduced with lentivectors expressing either green fluorescent protein (GFP) (Lenti-SP-GFP, control) or LXR alpha (Lenti-SP-LXR alpha) driven by a synthetic macrophage promoter. At 4 weeks post-transplant, the mice were fed with a Western diet for 8 weeks and then killed. Compared with Lenti-SP-GFP mice, the Lenti-SP-LXR alpha mice had a 30% reduction in atherosclerotic lesions, which was accompanied by increases in levels of macrophage expression of cholesterol efflux genes apolipoprotein E and ATP-binding cassette A1, as well as decreases in plasma inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha. Intriguingly, a 50% reduction of plasma triglyceride level was also observed. We conclude that HSC-based macrophage LXR alpha gene therapy ameliorates the development of atherosclerosis along with an unexpected concomitant reduction of plasma triglyceride levels in LDLR-/- mice. These findings highlight the potential value of macrophage LXR expression as an avenue for therapeutic intervention against atherosclerosis. Gene Therapy (2011) 18, 835-841; doi:10.1038/gt.2011.29; published online 10 March 2011