磷脂纳米粒：通过减少胆固醇晶体和抑制炎症来对抗动脉粥样硬化的治疗潜力。
Phospholipid nanoparticles: Therapeutic potentials against atherosclerosis via reducing cholesterol crystals and inhibiting inflammation.
机构信息
Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Second Xiangya Hospital, Central South University, Hunan Province, China.
Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
出版信息
EBioMedicine. 2021 Dec;74:103725. doi: 10.1016/j.ebiom.2021.103725. Epub 2021 Dec 6.
BACKGROUND
Atherosclerosis-related cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. Cholesterol crystals (CCs) induce inflammation in atherosclerosis and are associated with unstable plaques and poor prognosis, but no drug can remove CCs in the clinic currently.
METHODS
We generated a phospholipid-based and high-density lipoprotein (HDL)-like nanoparticle, miNano, and determined CC-dissolving capacity, cholesterol efflux property, and anti-inflammation effects of miNano in vitro. Both normal C57BL/6J and Apoe-deficient mice were used to explore the accumulation of miNano in atherosclerotic plaques. The efficacy and safety of miNano administration to treat atherosclerosis were evaluated in the Ldlr-deficient atherosclerosis model. The CC-dissolving capacity of miNano was also detected using human atherosclerotic plaques ex vivo.
FINDINGS
We found that miNano bound to and dissolved CCs efficiently in vitro, and miNano accumulated in atherosclerotic plaques, co-localized with CCs and macrophages in vivo. Administration of miNano inhibited atherosclerosis and improved plaque stability by reducing CCs and macrophages in Ldlr-deficient mice with favorable safety profiles. In macrophages, miNano prevented foam cell formation by enhancing cholesterol efflux and suppressed inflammatory responses via inhibiting TLR4-NF-κB pathway. Finally, in an ex vivo experiment, miNano effectively dissolved CCs in human aortic atherosclerotic plaques.
INTERPRETATION
Together, our work finds that phospholipid-based and HDL-like nanoparticle, miNano, has the potential to treat atherosclerosis by targeting CCs and stabilizing plaques.
FUNDING
This work was supported by the National Institutes of Health HL134569, HL109916, HL136231, and HL137214 to Y.E.C, HL138139 to J.Z., R21NS111191 to A.S., by the American Heart Association 15SDG24470155, Grant Awards (U068144 from Bio-interfaces and G024404 from M-BRISC) at the University of Michigan to Y.G., by the American Heart Association 19PRE34400017 and Rackham Helen Wu award to M.Y., NIH T32 GM07767 to K. H., Barbour Fellowship to D.L.
背景
与动脉粥样硬化相关的心血管疾病（CVDs）是全球范围内死亡的主要原因。胆固醇晶体（CCs）在动脉粥样硬化中引发炎症，与不稳定斑块和预后不良有关，但目前临床上尚无药物可去除 CCs。
方法
我们生成了一种基于磷脂的高密度脂蛋白（HDL）样纳米颗粒 miNano，并在体外测定了其溶解 CC 的能力、胆固醇外排能力和抗炎作用。我们使用正常的 C57BL/6J 和 Apoe 缺陷小鼠来研究 miNano 在动脉粥样硬化斑块中的积累。在 Ldlr 缺陷型动脉粥样硬化模型中评估了 miNano 给药治疗动脉粥样硬化的疗效和安全性。还使用人动脉粥样硬化斑块进行了体外检测 miNano 溶解 CC 的能力。
结果
我们发现 miNano 在体外能有效结合并溶解 CCs，miNano 在体内也能在动脉粥样硬化斑块中积累，与斑块中的 CCs 和巨噬细胞共定位。miNano 给药可减少 Ldlr 缺陷小鼠中的 CCs 和巨噬细胞，抑制动脉粥样硬化形成，改善斑块稳定性，具有良好的安全性。在巨噬细胞中，miNano 通过增强胆固醇外排和抑制 TLR4-NF-κB 通路来抑制炎症反应，从而阻止泡沫细胞形成。最后，在一项离体实验中，miNano 有效地溶解了人主动脉粥样硬化斑块中的 CCs。
结论
总之，我们的工作发现，基于磷脂的 HDL 样纳米颗粒 miNano 通过靶向 CCs 和稳定斑块，具有治疗动脉粥样硬化的潜力。
资助
这项工作得到了美国国立卫生研究院（NIH）HL134569、HL109916、HL136231 和 HL137214 资助（用于 Y.E.C），HL138139 资助（用于 J.Z.），R21NS111191 资助（用于 A.S.），美国心脏协会 15SDG24470155、密歇根大学 Bio-interfaces 和 M-BRISC 项目 Grant Awards（U068144 和 G024404）资助（用于 Y.G.），美国心脏协会 19PRE34400017 和 Rackham Helen Wu 奖（用于 M.Y.），NIH T32 GM07767 资助（用于 K.H.）和 Barbour Fellowship 资助（用于 D.L.）。
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