Macrophage Mitochondrial Energy Status Regulates Cholesterol Efflux and Is Enhanced by Anti-miR33 in Atherosclerosis.
Macrophage Mitochondrial Energy Status Regulates Cholesterol Efflux and Is Enhanced by Anti-miR33 in Atherosclerosis.
复制标题
巨噬细胞线粒体能量状态调节胆固醇外排，并在动脉粥样硬化中通过抗MIR33增强。
DOI：
10.1161/circresaha.117.305624
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发表时间：
2015-07-17
影响因子：
20.1
通讯作者：
Rayner KJ
中科院分区：
文献类型：
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作者：
Karunakaran D;Thrush AB;Nguyen MA;Richards L;Geoffrion M;Singaravelu R;Ramphos E;Shangari P;Ouimet M;Pezacki JP;Moore KJ;Perisic L;Maegdefessel L;Hedin U;Harper ME;Rayner KJ
以巨噬细胞为靶点的胆固醇逆向转运是治疗动脉粥样硬化的一种很有前途的方法。巨噬细胞的能量代谢可以显著影响巨噬细胞的表型，但这在泡沫细胞中是如何控制的尚不清楚。生物信息学途径分析预测，miR-33抑制一组控制细胞能量代谢的基因，这些基因在巨噬细胞胆固醇流出中可能很重要。我们假设细胞能量状态可以影响巨噬细胞的胆固醇流出，并且miR-33通过抑制线粒体能量代谢途径减少胆固醇流出。在这项研究中，我们证明了巨噬细胞胆固醇流出受线粒体ATP产生的调节，并且miR-33控制着同步线粒体功能的基因网络。线粒体ATP合酶的抑制显著降低巨噬细胞胆固醇流出能力，并且抗miR 33需要全功能线粒体来增强ABCA 1介导的胆固醇流出。具体而言，抗miR 33去抑制新的靶基因PGC-1α、PDK 4和SLC 25 A25，并促进线粒体呼吸和ATP的产生。与对照组相比，用抗miR 33寡核苷酸治疗动脉粥样硬化Apoe-/-小鼠减少了主动脉窦病变面积，尽管HDL-C或其他循环脂质没有变化。与正常动脉相比，人颈动脉粥样硬化斑块中miR-33 a/B的表达显著增加，并且伴随着线粒体调控基因PGC-1α、SLC 25 A25、NRF 1和TFAM的减少，表明这些基因与人类晚期动脉粥样硬化相关。这项研究表明，抗miR 33治疗去抑制增强线粒体呼吸和ATP产生的基因，这与ABCA 1表达增加相结合，促进巨噬细胞胆固醇流出并减少动脉粥样硬化。
Therapeutically targeting macrophage reverse cholesterol transport is a promising approach to treat atherosclerosis. Macrophage energy metabolism can significantly influence macrophage phenotype, but how this is controlled in foam cells is not known. Bioinformatic pathway analysis predicts that miR-33 represses a cluster of genes controlling cellular energy metabolism that may be important in macrophage cholesterol efflux. We hypothesized that cellular energy status can influence cholesterol efflux from macrophages, and that miR-33 reduces cholesterol efflux via repression of mitochondrial energy metabolism pathways. In this study, we demonstrated that macrophage cholesterol efflux is regulated by mitochondrial ATP production, and that miR-33 controls a network of genes that synchronize mitochondrial function. Inhibition of mitochondrial ATP synthase markedly reduces macrophage cholesterol efflux capacity, and anti-miR33 required fully functional mitochondria to enhance ABCA1-mediated cholesterol efflux. Specifically, anti-miR33 de-repressed the novel target genes PGC-1α, PDK4 and SLC25A25 and boosted mitochondrial respiration and production of ATP. Treatment of atherosclerotic Apoe-/- mice with anti-miR33 oligonucleotides reduced aortic sinus lesion area compared to controls, despite no changes in HDL-C or other circulating lipids. Expression of miR-33a/b was markedly increased in human carotid atherosclerotic plaques compared to normal arteries, and there was a concomitant decrease in mitochondrial regulatory genes PGC-1α, SLC25A25, NRF1 and TFAM, suggesting these genes are associated with advanced atherosclerosis in humans. This study demonstrates that anti-miR33 therapy de-represses genes that enhance mitochondrial respiration and ATP production, which in conjunction with increased ABCA1 expression, works to promote macrophage cholesterol efflux and reduce atherosclerosis.