Pulmonary Hypertension Research Group, Quebec Heart and Lung Institute Research Centre (IUCPQ), Québec City, Québec, Canada.
Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan.
Am J Respir Cell Mol Biol. 2023 May;68(5):537-550. doi: 10.1165/rcmb.2022-0300OC.
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 (G9a-like protein) have been shown to exert oncogenic effects and to serve as a buffer against an exaggerated transcriptional response. Therefore, we hypothesized that upregulation of G9a and GLP in PAH plays a pivotal role in pulmonary vascular remodeling by maintaining the abnormal phenotype of PAH-PASMCs. We found that G9a is increased in PASMCs from patients with PAH as well as in remodeled PAs from animal models. Pharmacological inhibition of G9a/GLP activity using BIX01294 and UNC0642 significantly reduced the prosurvival and proproliferative 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.
肺动脉高压（PAH）的特征是小肺动脉（PAs）的进行性血管重构，导致 PA 压持续升高、右心衰竭和死亡。与癌细胞类似，在应激状态下，参与肺血管重构的肺动脉平滑肌细胞（PASMCs）采用了多种机制来维持其存活和增殖。组蛋白甲基转移酶 G9a 及其伴侣蛋白 GLP（G9a 样蛋白）已被证明具有致癌作用，并作为缓冲物来对抗过度的转录反应。因此，我们假设 PAH 中 G9a 和 GLP 的上调通过维持 PAH-PASMCs 的异常表型在肺血管重构中起关键作用。我们发现，PAH 患者的 PASMCs 以及动物模型中重构的 PA 中 G9a 增加。使用 BIX01294 和 UNC0642 抑制 G9a/GLP 活性可显著降低培养的 PAH-PASMCs 的促生存和促增殖潜力。通过 RNA 测序进一步探索发现，G9a/GLP 促进细胞外基质的产生，并提供对过度活跃的应激反应的负面影响的保护。最后，我们发现 BIX01294 的治疗性治疗可减少肺动脉重构并降低幼鹿高血压大鼠的平均 PA 压。用 BIX01294 治疗 Sugen/低氧挑战的小鼠也改善了肺血流动力学和右心功能。总之，这些发现表明 G9a/GLP 抑制可能代表 PAH 的一种新的治疗方法。
