肺动脉高压（PAH）的特征在于小肺动脉（PAs）的进行性血管重构，导致持续性PA压力升高、右心室功能衰竭和死亡。类似于癌细胞，对于肺血管重构起关键作用的血管平滑肌细胞（PASMCs）在受到压力刺激时采取了多种机制来维持其生存和增殖。组蛋白甲基转移酶G9a及其合作蛋白GLP已被证明具有致癌作用，并且可以作为对过度转录响应的缓冲。因此，我们假设，在PAH中G9a/GLP的上调通过维持PAH-PASMCs的异常表型在肺血管重构中发挥关键作用。我们发现，G9a在PAH患者的PASMCs以及动物模型的重构PA中均增加了。药理学上抑制G9a/GLP活性使用BIX01294和UNC0642可显著减少培养的PAH-PASMCs的抗死和增殖作用。通过RNA测序，进一步探索显示G9a/GLP促进细胞外基质的产生并保护免受过度应激响应的负面影响。最后，我们发现，使用BIX01294的治疗减少了Fawn-Hooded大鼠的肺血管重构并降低了平均PA压力。使用BIX01294治疗Sugen/低氧挑战小鼠还改善了肺血液动力学和右心室功能。总之，这些发现表明G9a / GLP抑制可能代表了PAH的一种新的治疗方法。

Pulmonary arterial hypertension (PAH) is characterized by progressive vascular remodeling of small pulmonary arteries (PAs) causing sustained elevation of PA pressure, right ventricular failure and death. Similar to cancer cells, PA smooth muscle cells (PASMCs), which play a key role in pulmonary vascular remodeling, have adopted multiple mechanisms to sustain their survival and proliferation in the presence of stress. The histone methyltransferase G9a and its partner protein GLP have been shown to exert oncogenic effects and to serve as a buffer against an exaggerated transcriptional response. Therefore, we hypothesized that up-regulation of G9a/GLP in PAH plays a pivotal role in pulmonary vascular remodeling by maintaining the abnormal phenotype of PAH-PASMCs. We found that G9a is increases in PASMCs from PAH patients as well as in remodeled PAs from animal models. Pharmacological inhibition of G9a/GLP activity using BIX01294 and UNC0642 significantly reduced the pro-survival and pro-proliferative potentials of cultured PAH-PASMCs. Using RNA sequencing, further exploration revealed that G9a/GLP promotes extracellular matrix production and affords protection against the negative effects of an overactive stress response. Finally, we found that therapeutic treatment with BIX01294 reduced pulmonary vascular remodeling and lowered mean PA pressure in Fawn-Hooded rats. Treatment of Sugen/hypoxia-challenged mice with BIX01294 also improved pulmonary hemodynamics and right ventricular function. In conclusion, these findings indicate that G9a/GLP inhibition may represent a new therapeutic approach in PAH.