Ubiquitinated ligation protein NEDD4L participates in MiR-30a-5p attenuated atherosclerosis by regulating macrophage polarization and lipid metabolism.
Ubiquitinated ligation protein NEDD4L participates in MiR-30a-5p attenuated atherosclerosis by regulating macrophage polarization and lipid metabolism.
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DOI：
10.1016/j.omtn.2021.10.030
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发表时间：
2021-12-03
期刊：
影响因子：
--
通讯作者：
Li G
中科院分区：
文献类型：
--
作者：
Song F;Li JZ;Wu Y;Wu WY;Wang Y;Li G
MiR-30a-5p在多种心血管疾病中发挥重要作用，但其在动脉粥样硬化中的作用尚未见报道。使用载脂蛋白 E 缺陷 (Apo E−/−) 小鼠研究 miR-30a-5p 在动脉粥样硬化中的作用，并在体内和体外研究其潜在机制。荧光原位杂交测试显示miR-30a-5p在Apo E−/−小鼠病灶中表达。然而，在RAW264.7巨噬细胞中，脂多糖（LPS）或氧化低密度脂蛋白降低了miR-30a-5p的表达。 MiR-30a-5p-ago 治疗的 Apo E−/− 小鼠显着减少了主动脉和主动脉根部的病变面积，降低了脂蛋白和促炎细胞因子的水平，并增加了抗炎细胞因子的水平。通过调节 Smad-1/2 磷酸化，miR-30a-5p-ago 处理的 Apo E−/− 小鼠和 LPS 处理的 RAW264.7 巨噬细胞中 M1/M2 巨噬细胞的比例降低。 MiR-30a-5p 通过调节 PPAR-γ、ABCA1、ABCG1、LDLR 和 PCSK9 的表达来减少氧化低密度脂蛋白处理的巨噬细胞的脂质摄取。泛素化连接酶 NEDD4L 被确定为 miR-30a-5p 的靶标。有趣的是，敲低 NEDD4L 通过抑制 PPAR-γ 泛素化和 Smad-1/2 磷酸化以及调节 ABCA1、ABCG1、LDLR 和 PCSK9 来降低巨噬细胞中 M1/M2 比值和氧化低密度脂蛋白摄取。我们证明了 miR-30a-5p 在动脉粥样硬化中的新作用和机制。 MiR-30a-5p 通过调节 M1/M2 巨噬细胞的极化和脂质代谢来减轻动脉粥样硬化并降低血清脂质和促炎细胞因子。泛素化连接酶 NEDD4L 是 miR-30a-5p 的靶标，通过介导 PPAR-γ 泛素化和 Smad-1/2 磷酸化，参与 miR-30a-5p 调节的脂质代谢和 M1/M2 巨噬细胞极化。
MiR-30a-5p plays an important role in various cardiovascular diseases, but its effect in atherosclerosis has not been reported. Apolipoprotein E-deficient (Apo E−/−) mice were used to investigate the role of miR-30a-5p in atherosclerosis, and the underlying mechanism was investigated in vivo and in vitro. The fluorescence in situ hybridization test revealed that miR-30a-5p was expressed in Apo E−/− mice lesions. Nevertheless, in RAW264.7 macrophages, the expression of miR-30a-5p was reduced by lipopolysaccharide (LPS) or oxidized low-density lipoprotein. MiR-30a-5p-ago-treated Apo E−/− mice significantly reduced lesion areas in the aorta and aortic root, reduced levels of lipoprotein and pro-inflammatory cytokines, and increased levels of anti-inflammatory cytokines. The ratio of M1/M2 macrophages was decreased in miR-30a-5p-ago-treated Apo E−/− mice and LPS-treated RAW264.7 macrophages by the regulation of Smad-1/2 phosphorylation. MiR-30a-5p reduced lipid uptake in oxidized low-density lipoprotein-treated macrophages by regulating the expression of PPAR-γ, ABCA1, ABCG1, LDLR, and PCSK9. Ubiquitinated ligase NEDD4L was identified as a target of miR-30a-5p. Interestingly, knockdown of NEDD4L decreased the M1/M2 ratio and oxidized low-density lipoprotein uptake in macrophages by inhibiting the ubiquitination of PPAR-γ and phosphorylation of Smad-1/2 and regulating ABCA1, ABCG1, LDLR, and PCSK9. We demonstrated a novel effect and mechanism of miR-30a-5p in atherosclerosis. MiR-30a-5p attenuates atherosclerosis and decreases serum lipid and pro-inflammatory cytokines by regulating the polarization of M1/M2 macrophages and lipid metabolism. The ubiquitination ligase NEDD4L is a target of miR-30a-5p, which participates in miR-30a-5p-regulated lipid metabolism and M1/M2 macrophage polarization by mediating the ubiquitination of PPAR-γ and phosphorylation of Smad-1/2.
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