MicroRNA-302a promotes neointimal formation following carotid artery injury in mice by targeting PHLPP2 thus increasing Akt signaling
MicroRNA-302a promotes neointimal formation following carotid artery injury in mice by targeting PHLPP2 thus increasing Akt signaling
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MicroRNA-302a 通过靶向 PHLPP2 促进小鼠颈动脉损伤后的新内膜形成，从而增强 Akt 信号传导
DOI：
10.1038/s41401-020-0440-4
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发表时间：
2020-07-21
影响因子：
8.2
通讯作者：
Liang, Si-jia
中科院分区：
文献类型：
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作者：
Liu, Ying-ying;Liu, Xiu;Liang, Si-jia
平滑肌细胞过度增殖和迁移在经皮冠状动脉介入治疗后再狭窄中起重要作用。MicroRNA能够靶向多种基因，并参与调节包括细胞生长和增殖在内的多种细胞过程。在这项研究中，我们研究了microRNA是否以及如何调节小鼠颈动脉损伤后血管SMC增殖和血管重塑。我们发现，在microRNA（miR）-302杂合小鼠和SMC特异性miR-302敲除小鼠中，颈动脉损伤诱导的新生内膜形成显著改善。相比之下，将miR-302a腺病毒递送至损伤的颈动脉增强了新生内膜形成。上调miR-302a可通过促进细胞周期转换增强体外培养的小鼠主动脉平滑肌细胞（MASMC）的增殖和迁移，而抑制miR-302a则导致相反的结果。此外，miR-302a通过共同降低MASMC中Akt表达和增加Akt磷酸化来促进Akt活化。应用Akt抑制剂GSK690693（5 μ mol/L）可阻断miR-302a促进MASMC增殖和迁移的作用。miR-302a直接作用于PH结构域的3 ′端非翻译区和富含亮氨酸重复序列的蛋白磷酸酶2（PHLPP 2），负调控PHLPP 2的表达。PHLPP2的恢复消除了miR-302a对Akt激活和MASMC运动的影响。此外，PHLPP2的敲低在很大程度上消除了在miR-302杂合小鼠中观察到的对新生内膜形成的抑制。我们的数据表明，miR-302a通过靶向PHLPP2增加Akt信号传导而加剧SMC增殖和再狭窄。
The excessive proliferation and migration of smooth muscle cells (SMCs) play an important role in restenosis following percutaneous coronary interventions. MicroRNAs are able to target various genes and involved in the regulation of diverse cellular processes including cell growth and proliferation. In this study we investigated whether and how MicroRNAs regulated vascular SMC proliferation and vascular remodeling following carotid artery injury in mice. We showed that carotid artery injury-induced neointimal formation was remarkably ameliorated in microRNA (miR)-302 heterozygous mice and SMC-specific miR-302 knockout mice. In contrast, delivery of miR-302a adenovirus to the injured carotid artery enhanced neointimal formation. Upregulation of miR-302a enhanced the proliferation and migration of mouse aorta SMC (MASMC) in vitro by promoting cell cycle transition, whereas miR-302a inhibition caused the opposite results. Moreover, miR-302a promoted Akt activation by corporately decreasing Akt expression and increasing Akt phosphorylation in MASMCs. Application of the Akt inhibitor GSK690693 (5 μmol/L) counteracted the functions of miR-302a in promoting MASMC proliferation and migration. We further revealed that miR-302a directly targeted at the 3′ untranslated region of PH domain and leucine rich repeat protein phosphatase 2 (PHLPP2) and negatively regulated PHLPP2 expression. Restoration of PHLPP2 abrogated the effects of miR-302a on Akt activation and MASMC motility. Furthermore, knockdown of PHLPP2 largely abolished the inhibition of neointimal formation that was observed in miR-302 heterozygous mice. Our data demonstrate that miR-302a exacerbates SMC proliferation and restenosis through increasing Akt signaling by targeting PHLPP2.