Zhang Chen, Sun Yue, Guo Yingying, Xu Jingjing, Zhao Haiyan
Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
Department of Rheumatology and Immunology, Shengjing Hospital of China Medical University, Shenyang, China.
Cell Death Discov. 2023 Mar 18;9(1):98. doi: 10.1038/s41420-023-01390-5.
Pulmonary arterial hypertension (PAH) is a chronic disorder characterized by hyperproliferation of pulmonary arterial smooth muscle cells (PASMCs). JMJD1C, a member of the Jumonji domain containing C (JMJC) histone demethylase family, contributes to cardiovascular dysfunction. However, the role of JMJD1C in PAH remains unknown. Mice were exposed to hypoxia to mimic several features associated with PAH clinically. We found that JMJD1C was highly expressed in the lungs of mice after hypoxia exposure. JMJD1C knockdown ameliorated hypoxia-induced right ventricular remodeling and thickening of the pulmonary arterial wall. PASMC hyperproliferation and resistance to apoptosis in mice exposed to hypoxia were suppressed by JMJD1C inhibition. We demonstrated that JMJD1C silencing reduced glycolytic enzymes (HK2, PGK1 and LDHA) and lactate overaccumulation in the lungs of mice exposed to hypoxia. In vitro, hypoxia-induced hyperproliferation and activated glycolytic processes in mouse PASMCs were impaired by JMJD1C knockdown. In addition, the activation of STAT3 signaling by hypoxia was suppressed by JMJD1C silencing both in vivo and in vitro. The overexpression of STAT3 reversed the inhibitory effect of JMJD1C depletion on proliferation and glycolysis in PASMCs under hypoxia. Thus, JMJD1C induces glycolytic processes by activating STAT3 signaling to promote PASMC proliferation and pulmonary vascular remodeling, suggesting the potential role of JMJD1C in regulating the metabolic program and vascular remodeling in PAH.
肺动脉高压（PAH）是一种以肺动脉平滑肌细胞（PASMCs）过度增殖为特征的慢性疾病。Jumonji结构域含C（JMJC）组蛋白去甲基化酶家族成员JMJD1C会导致心血管功能障碍。然而，JMJD1C在PAH中的作用尚不清楚。将小鼠暴露于低氧环境以模拟临床上与PAH相关的一些特征。我们发现，低氧暴露后小鼠肺中JMJD1C高表达。敲低JMJD1C可改善低氧诱导的右心室重塑和肺动脉壁增厚。抑制JMJD1C可抑制低氧暴露小鼠的PASMC过度增殖和对凋亡的抵抗。我们证明，敲低JMJD1C可减少低氧暴露小鼠肺中的糖酵解酶（HK2、PGK1和LDHA）和乳酸过度积累。在体外，敲低JMJD1C可损害低氧诱导的小鼠PASMC过度增殖和激活的糖酵解过程。此外，体内和体外实验均表明，敲低JMJD1C可抑制低氧对STAT3信号的激活。STAT3的过表达逆转了JMJD1C缺失对低氧条件下PASMC增殖和糖酵解的抑制作用。因此，JMJD1C通过激活STAT3信号诱导糖酵解过程，以促进PASMC增殖和肺血管重塑，提示JMJD1C在调节PAH的代谢程序和血管重塑中具有潜在作用。
