NSD2 silencing alleviates pulmonary arterial hypertension by inhibiting trehalose metabolism and autophagy
NSD2 silencing alleviates pulmonary arterial hypertension by inhibiting trehalose metabolism and autophagy
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NSD2沉默通过抑制海藻糖代谢和自噬减轻肺动脉高压
DOI：
10.1042/cs20190142
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发表时间：
2019
期刊：
影响因子：
6
通讯作者：
Liu Ji chun
中科院分区：
文献类型：
--
作者：
Zhou Xue liang;Liu Zhi bo;Zhu Rong rong;Huang Huang;Xu Qi rong;Xu Hua;Zeng Liang;Li Yun yun;Huang Cha hua;Wu Qi cai;Liu Ji chun
核受体结合SET结构域2（NSD 2）介导的代谢重编程已被证明通过催化组蛋白甲基化来调节肿瘤发生。本研究旨在探讨NSD 2介导的代谢异常在肺动脉高压（PAH）中的作用。建立野百合碱（MCT）诱导的PAH大鼠模型，用携带靶向NSD 2的短发夹状RNA（shRNA）的腺相关病毒感染PAH大鼠。通过微导管、超声心动图和组织学分析评价血流动力学参数、心室功能和病理学。通过LC-MS分析肺组织中的代谢组学变化。结果表明，沉默NSD 2基因可有效改善MCT诱导的肺动脉高压和右心室功能障碍，部分逆转肺动脉病理性重构和右心室肥厚。此外，NSD 2基因沉默还能显著降低H3 K36的去甲基化水平（H3 K36 me 2水平），抑制肺动脉自噬。基于非靶向LC-MS的代谢组学分析表明，海藻糖在肺组织中显示出最显著的变化。NSD 2调节的海藻糖主要影响ABC转运蛋白、矿物质吸收、蛋白质消化和吸收、代谢途径和氨酰-tRNA生物合成。总之，我们揭示了NSD 2在PAH发病机制中的新作用，其通过增加H3 K36 me 2水平来调节海藻糖代谢和自噬。NSD 2是PAH治疗的一个有希望的靶点。
Nuclear receptor binding SET domain 2 (NSD2)-mediated metabolic reprogramming has been demonstrated to regulate oncogenesis via catalyzing the methylation of histones. The present study aimed to investigate the role of NSD2-mediated metabolic abnormality in pulmonary arterial hypertension (PAH). Monocrotaline (MCT)-induced PAH rat model was established and infected with adeno-associated virus carrying short hairpin RNA (shRNA) targeting NSD2. Hemodynamic parameters, ventricular function, and pathology were evaluated by microcatheter, echocardiography, and histological analysis. Metabolomics changes in lung tissue were analyzed by LC–MS. The results showed that silencing of NSD2 effectively ameliorated MCT-induced PAH and right ventricle dysfunction, and partially reversed pathological remodeling of pulmonary artery and right ventricular hypertrophy. In addition, the silencing of NSD2 markedly reduced the di-methylation level of H3K36 (H3K36me2 level) and inhibited autophagy in pulmonary artery. Non-targeted LC–MS based metabolomics analysis indicated that trehalose showed the most significant change in lung tissue. NSD2-regulated trehalose mainly affected ABC transporters, mineral absorption, protein digestion and absorption, metabolic pathways, and aminoacyl-tRNA biosynthesis. In conclusion, we reveal a new role of NSD2 in the pathogenesis of PAH related to the regulation of trehalose metabolism and autophagy via increasing the H3K36me2 level. NSD2 is a promising target for PAH therapy.