Macrophage NCOR1 Deficiency Ameliorates Myocardial Infarction and Neointimal Hyperplasia in Mice.
Macrophage NCOR1 Deficiency Ameliorates Myocardial Infarction and Neointimal Hyperplasia in Mice.
复制标题
巨噬细胞 NCOR1 缺陷可改善小鼠心肌梗死和新内膜增生
DOI：
10.1161/jaha.120.015862
复制
发表时间：
2020-08-04
影响因子：
5.4
通讯作者：
Duan SZ
中科院分区：
文献类型：
--
作者：
Du LJ;Sun JY;Zhang WC;Wang YL;Zhu H;Liu T;Gao MZ;Zheng C;Zhang YY;Liu Y;Liu Y;Shao S;Zhang XQ;Leng Q;Auwerx J;Duan SZ
核受体辅阻遏物1（nuclear receptor corepressor 1，NCOR 1）是基因转录的重要辅调节因子。研究表明，巨噬细胞中的NCOR 1在代谢调节中起重要作用。然而，巨噬细胞NCOR 1在响应心肌梗死（MI）或血管丝损伤中的功能尚未阐明。方法和结果在这里，使用巨噬细胞NCOR 1基因敲除小鼠与MI小鼠模型相结合，我们证明了巨噬细胞NCOR 1缺陷显着减少心肌梗死面积和改善心肌梗死后的心脏功能。此外，巨噬细胞NCOR 1缺陷显著抑制动脉丝损伤小鼠模型中的新生内膜增生和血管重塑。炎症和巨噬细胞增殖显着减弱心肌梗死和动脉丝损伤后，分别在心脏和动脉的巨噬细胞Ncor 1基因敲除小鼠。来自巨噬细胞Ncor 1敲除小鼠的培养的原代巨噬细胞在白细胞介素-1 β、白细胞介素-6或脂多糖刺激后表现出较低的炎性基因表达，以及炎症信号级联反应（包括信号转导和转录激活因子1和核因子-κB）的活化少得多。此外，与对照细胞相比，巨噬细胞Ncor 1敲除巨噬细胞在培养中增殖性低得多，细胞周期进程受到抑制。结论：总的来说，我们的数据表明，NCOR 1是巨噬细胞炎症和增殖的关键调节因子，巨噬细胞中NCOR 1的缺乏可减轻MI和新生内膜增生。因此，巨噬细胞NCOR 1可能作为MI和再狭窄的潜在治疗靶点。
Background NCOR1 (nuclear receptor corepressor 1) is an essential coregulator of gene transcription. It has been shown that NCOR1 in macrophages plays important roles in metabolic regulation. However, the function of macrophage NCOR1 in response to myocardial infarction (MI) or vascular wire injury has not been elucidated. Methods and Results Here, using macrophage Ncor1 knockout mouse in combination with a mouse model of MI, we demonstrated that macrophage NCOR1 deficiency significantly reduced infarct size and improved cardiac function after MI. In addition, macrophage NCOR1 deficiency markedly inhibited neointimal hyperplasia and vascular remodeling in a mouse model of arterial wire injury. Inflammation and macrophage proliferation were substantially attenuated in hearts and arteries of macrophage Ncor1 knockout mice after MI and arterial wire injury, respectively. Cultured primary macrophages from macrophage Ncor1 knockout mice manifested lower expression of inflammatory genes upon stimulation by interleukin‐1β, interleukin‐6, or lipopolysaccharide, together with much less activation of inflammatory signaling cascades including signal transducer and activator of transcription 1 and nuclear factor‐κB. Furthermore, macrophage Ncor1 knockout macrophages were much less proliferative in culture, with inhibited cell cycle progression compared with control cells. Conclusions Collectively, our data have demonstrated that NCOR1 is a critical regulator of macrophage inflammation and proliferation and that deficiency of NCOR1 in macrophages attenuates MI and neointimal hyperplasia. Therefore, macrophage NCOR1 may serve as a potential therapeutic target for MI and restenosis.