Human MicroRNA-33b Promotes Atherosclerosis in Apoe-/- Mice.
Human MicroRNA-33b Promotes Atherosclerosis in Apoe-/- Mice.
复制标题
人类 MicroRNA-33b 促进 Apoe-/- 小鼠的动脉粥样硬化。
DOI：
10.1161/atvbaha.118.311617
复制
发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Goldberg,IraJ
中科院分区：
文献类型：
--
作者：
Hussain,MMahmood;Goldberg,IraJ
Hussain和Goldberg MiR-33 b和Atherosin 2273将巨噬细胞胆固醇移动到血清中。这些研究指出了人miR-33 b的功能性表达及其调节小鼠胆固醇代谢的能力。Nishino等人19还研究了miR-33 b对巨噬细胞功能的影响。与对照组相比，乙酰化LDL处理的MIR 33 BKI +/+ Apoe−/−腹腔巨噬细胞中ABCA 1/ABCG 1的诱导受到抑制。此外，MIR 33 BKI +/+ Apoe−/−巨噬细胞显示出减少的胆固醇流出至apoA 1和HDL。当ACAT活性被抑制时，这些腹腔巨噬细胞也显示出凋亡增加。因此，很可能miR-33 b表达降低了ABCA 1/ABCG 1的表达，减少了胆固醇流出，并增加了对腹腔巨噬细胞中游离胆固醇同化的敏感性。miR-33 b表达显著增加巨噬细胞炎症反应。诱导的腹膜MIR 33 BKI +/+ A poe−/−巨噬细胞显示促炎性IL（白细胞介素）-1β、IL-6和CCL 2细胞因子的产生增加。在THP-1细胞中的进一步研究表明，miR-33 B的表达增加了使用霍乱毒素亚基B可检测到的脂筏。在用环糊精处理以去除胆固醇和减弱促炎细胞因子的产生后，这些筏可以减少。因此，miR-33 b可能会增加细胞膜中游离胆固醇的积累、脂筏的形成和促炎细胞因子的产生。对分离的腹腔巨噬细胞的研究清楚地表明，miR-33 b对胆固醇流出和炎症反应具有显著影响。为了确定骨髓衍生的巨噬细胞是否具有类似的缺陷，进行了骨髓移植研究。接受MIR 33 BKI +/+ Apoe−/−小鼠骨髓细胞的小鼠显示出更大的斑块面积和更多的巨噬细胞含量。这些移植研究对血浆胆固醇水平没有影响。因此，表达miR-33 b的骨髓来源细胞促进动脉粥样硬化，而不依赖于调节血浆HDL胆固醇水平。令人惊讶的是，Mir 33 bKI +/+ Apoe−/−小鼠的血浆甘油三酯水平较低。为了解释低血浆甘油三酯水平，研究人员测量了肝素可释放脂肪酶活性，发现脂肪酶活性不受miR-33 b的影响。此外，apoC 2、apoC 3、Gpihbp 1（糖基磷脂酰肌醇锚定的高密度脂蛋白结合蛋白1）、Angptl 3（血管生成素样3）、Angptl 4（血管生成素样4）和Angptl 8（血管生成素样8）的表达不受影响。因此，miR-33 b似乎不影响脂蛋白甘油三酯水解。脂蛋白生成研究表明，miR-33 b对VLDL生成没有影响。令人惊讶的是，他们观察到这些小鼠的脂质吸收较慢。脂质吸收减少可能导致血浆甘油三酯水平降低。需要更多的机制研究来找出miR-33 b如何以及为什么可能参与脂质吸收以及它如何影响整体血浆甘油三酯代谢。此外，这些研究需要在另一个模型系统中得到证实。在野生型背景的MIR 33 B +/−和MIR 33 B +/+小鼠中未观察到血浆甘油三酯降低。18同样与这些结果相反，在猴子中抑制miR-33 a/B降低了VLDL甘油三酯。15因此，MIR 33 BKI +/+ Apoe−/−小鼠血浆甘油三酯水平降低是否是由于基因-基因相互作用或继发于脂质吸收缺陷，仍有待确定。MIR 33 BKI +/+ Ldlr−/−小鼠的研究可能提供一些线索。或者研究可以在MIR 33 BKI +/+小鼠中进行注射。
Hussain and Goldberg MiR-33b and Atherosclerosis 2273 movement of macrophage cholesterol into the serum. These studies point to functional expression of human miR-33b and its ability to modulate mouse cholesterol metabolism. Nishino et al19 also studied the effect of miR-33b on macrophage function. Induction of ABCA1/ABCG1 was suppressed in MIR33BKI+/+ Apoe−/− peritoneal macrophages treated with acetylated LDL compared with controls. Further, MIR33BKI+/+ Apoe−/− macrophages showed reduced cholesterol efflux to apoA1 and HDL. These peritoneal macrophages also showed increased apoptosis when ACAT activity was inhibited. Thus, it is likely that miR-33b expression reduces expression of ABCA1/ABCG1, reduces cholesterol efflux, and increases sensitivity to free cholesterol assimilation in peritoneal macrophages. MiR-33b expression significantly increased macrophage inflammatory response. Elicited peritoneal MIR33BKI+/+ A poe−/− macrophages showed increased production of proinflammatory IL (interleukin)-1β, IL-6, and CCL2 cytokines. Further studies in THP-1 cells showed that expression of miR-33b increases lipid rafts detectable using cholera toxin subunit B. These rafts can be reduced after treatment with cyclodextrins to remove cholesterol and attenuate production of proinflammatory cytokines. Thus, miR-33b may enhance free cholesterol accumulation in plasma membrane, lipid rafts formation, and production of proinflammatory cytokines. The studies with isolated peritoneal macrophages clearly showed that miR-33b had significant effect on cholesterol efflux and inflammatory response. To determine whether bone marrow–derived macrophages have similar defects bone marrow transplantation studies were performed. Mice that received bone marrow cells from MIR33BKI+/+ Apoe−/− mice showed greater plaque areas and more macrophage content. These transplantation studies had no effect on plasma cholesterol levels. Thus, bone marrow–derived cells expressing miR-33b contribute to atherosclerosis independent of regulating plasma HDL cholesterol levels.Surprisingly, Mir33bKI+/+ Apoe−/− mice had low plasma triglyceride levels. 19 To explain low plasma triglyceride levels, investigators measured heparin-releasable lipase activity and found that lipase activity was unaffected by miR-33b. Further, expression of apoC2, apoC3, Gpihbp1 (glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1), Angptl3 (angiopoietin-like 3), Angptl4 (angiopoietin-like 4), and Angptl8 (angiopoietin-like 8) was unaffected. Thus, miR-33b does not seem to affect lipoprotein triglyceride hydrolysis. Lipoprotein production studies showed that miR-33b had no effect on VLDL production. Surprisingly, they observed slower lipid absorption in these mice. It is possible that reduced lipid absorption contributes to low plasma triglyceride levels. More mechanistic studies are needed to find out how and why miR-33b might be involved in lipid absorption and how it affects overall plasma triglyceride metabolism. Moreover, these studies need to be confirmed in another model system. Reductions in plasma triglycerides were not seen in MIR33B+/− and MIR33B+/+ mice on wild-type background. 18 Also in contrast to these results, inhibition of miR-33a/b in monkeys lowered VLDL triglyceride. 15 Therefore, it remains to be determined whether reduced plasma triglyceride levels in MIR33BKI+/+ Apoe−/− mice is because of gene-gene interactions or they are secondary to defective lipid absorption. Studies in MIR33BKI+/+ Ldlr−/− mice may provide some clues. Or studies can be performed in MIR33BKI+/+ mice injected …
登录
查看更多内容
影响因子：
4
作者：
Zhang X;Price NL;Fernández-Hernando C
通讯作者：
Fernández-Hernando C
影响因子：
20.1
作者：
Rayner KJ;Moore KJ
通讯作者：
Moore KJ
影响因子：
37.8
作者：
Takahiro Horie;Tomohiro Nishino;Osamu Baba;Y. Kuwabara;T. Nakao;M. Nishiga;S. Usami;M. Izuhara;Fumiko Nakazeki;Y. Ide;S. Koyama;M. Yokode;T. Kita;Takeshi Kimura;K. Ono
通讯作者：
Takahiro Horie;Tomohiro Nishino;Osamu Baba;Y. Kuwabara;T. Nakao;M. Nishiga;S. Usami;M. Izuhara;Fumiko Nakazeki;Y. Ide;S. Koyama;M. Yokode;T. Kita;Takeshi Kimura;K. Ono
影响因子：
8.8
作者：
Price NL;Rotllan N;Canfrán-Duque A;Zhang X;Pati P;Arias N;Moen J;Mayr M;Ford DA;Baldán Á;Suárez Y;Fernández-Hernando C
通讯作者：
Fernández-Hernando C
影响因子：
8.8
作者：
Price NL;Singh AK;Rotllan N;Goedeke L;Wing A;Canfrán-Duque A;Diaz-Ruiz A;Araldi E;Baldán Á;Camporez JP;Suárez Y;Rodeheffer MS;Shulman GI;de Cabo R;Fernández-Hernando C
通讯作者：
Fernández-Hernando C