Genetic deletion of CMG2 exacerbates systemic-to-pulmonary shunt-induced pulmonary arterial hypertension
Genetic deletion of CMG2 exacerbates systemic-to-pulmonary shunt-induced pulmonary arterial hypertension
复制标题
CMG2 基因缺失会加剧全身至肺分流引起的肺动脉高压
DOI：
10.1096/fj.202000299r
复制
发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Meng L;Yuan W;Chi H;Han R;Zhang Y;Pan X;Meng J;Liu Y;Song J;Zhong J;Liu X
继发于先天性心脏病（CHD-PAH）并伴有全身肺分流（SPS）的肺动脉高压（PAH）的特点是增殖性血管重塑。毛细血管形态发生基因-2 (CMG2) 在细胞增殖和凋亡中发挥关键作用。本研究旨在确定 CMG2 在 SPS 诱导的 PAH 发病机制中的作用。艾森曼格综合征患者和 SPS 诱导的 PAH 大鼠的肺小动脉中 CMG2 水平显着下调。 CMG2 在包括人肺动脉平滑肌细胞 (HPASMC) 在内的多种细胞中高表达。当暴露于 SPS 8 周时，CMG2−/− 大鼠比野生型大鼠表现出更严重的 PAH 和肺血管重塑。 CMG2的过表达显着抑制HPASMCs增殖并促进细胞凋亡，而CMG2的敲低则促进细胞增殖并抑制细胞凋亡。下一代测序和随后的验证结果表明，PI3K-AKT 是 CMG2−/− 大鼠肺中差异表达基因 (DEG) 调节的最重要的信号通路。我们的工作基于 CMG2 缺乏会加剧 SPS 诱导的 PAH 发生过程中的血管重塑这一发现，确定了 CMG2 在 SPS 诱导的 PAH 中的新作用，表明 CMG2 可能作为治疗 CHD-PAH 的潜在靶点。
Pulmonary arterial hypertension (PAH) secondary to congenital heart disease (CHD‐PAH) with systemic‐to‐pulmonary shunt (SPS) is characterized by proliferative vascular remodeling. Capillary morphogenesis gene‐2 (CMG2) plays a key role in cell proliferation and apoptosis. This study aimed to determine the role of CMG2 in the pathogenesis of SPS‐induced PAH. CMG2 levels were significantly downregulated in pulmonary arterioles from patients with Eisenmenger syndrome and rats with SPS‐induced PAH. CMG2 was highly expressed in several cells including human pulmonary arterial smooth muscle cells (HPASMCs). CMG2−/−rats exhibited more severe PAH and pulmonary vascular remodeling than wild‐type rats when exposed to SPS for 8 weeks. Overexpression of CMG2 significantly inhibited proliferation and promoted apoptosis of HPASMCs, while knockdown of CMG2 promoted cell proliferation and inhibited cell apoptosis. Next‐generation sequencing and subsequent validation results suggested that PI3K‐AKT was the most prominent signaling pathway regulated by differentially expressed genes (DEGs) in CMG2−/−rat lungs. Our work identified a novel role for CMG2 in SPS‐induced PAH based on the findings that CMG2 deficiency exacerbates SPS‐induced vascular remodeling in the development of PAH, indicating that CMG2 might act as a potential target for the treatment of CHD‐PAH.