Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany.
Department of Medicine Laval University, Pulmonary Hypertension and Vascular Biology Research Group of Quebec Heart and Lung Institute, G1V 4G5 Quebec, Canada.
Sci Transl Med. 2022 Jun 8;14(648):eabe5407. doi: 10.1126/scitranslmed.abe5407.
Phenotypic alterations in resident vascular cells contribute to the vascular remodeling process in diseases such as pulmonary (arterial) hypertension [P(A)H]. How the molecular interplay between transcriptional coactivators, transcription factors (TFs), and chromatin state alterations facilitate the maintenance of persistently activated cellular phenotypes that consequently aggravate vascular remodeling processes in PAH remains poorly explored. RNA sequencing (RNA-seq) in pulmonary artery fibroblasts (FBs) from adult human PAH and control lungs revealed 2460 differentially transcribed genes. Chromatin immunoprecipitation sequencing (ChIP-seq) revealed extensive differential distribution of transcriptionally accessible chromatin signatures, with 4152 active enhancers altered in PAH-FBs. Integrative analysis of RNA-seq and ChIP-seq data revealed that the transcriptional signatures for lung morphogenesis were epigenetically derepressed in PAH-FBs, including coexpression of T-box TF 4 (), , and SRY-box TF 9 (), which are involved in the early stages of lung development. These TFs were expressed in mouse fetuses and then repressed postnatally but were maintained in persistent PH of the newborn and reexpressed in adult PAH. Silencing of , , , or E1A-associated protein P300 () by RNA interference or small-molecule compounds regressed PAH phenotypes and mesenchymal signatures in arterial FBs and smooth muscle cells. Pharmacological inhibition of the P300/CREB-binding protein complex reduced the remodeling of distal pulmonary vessels, improved hemodynamics, and reversed established PAH in three rodent models in vivo, as well as reduced vascular remodeling in precision-cut tissue slices from human PAH lungs ex vivo. Epigenetic reactivation of TFs associated with lung development therefore underlies PAH pathogenesis, offering therapeutic opportunities.
在疾病（如肺动脉高压[PAH]）中，常驻血管细胞的表型改变导致血管重塑过程。转录共激活因子、转录因子（TFs）和染色质状态改变之间的分子相互作用如何促进持续激活的细胞表型的维持，从而加剧 PAH 中的血管重塑过程，这仍然知之甚少。从成人 PAH 和对照肺的肺动脉成纤维细胞（FB）中进行 RNA 测序（RNA-seq）揭示了 2460 个差异转录基因。染色质免疫沉淀测序（ChIP-seq）显示转录可及染色质特征的广泛差异分布，PAH-FB 中有 4152 个活跃增强子发生改变。RNA-seq 和 ChIP-seq 数据的综合分析表明，PAH-FB 中肺形态发生的转录特征被表观遗传去抑制，包括 T 盒 TF 4 (),, 和 SRY 盒 TF 9 () 的共表达，它们参与肺发育的早期阶段。这些 TF 在小鼠胎儿中表达，然后在出生后被抑制，但在新生儿持续 PH 中被维持，并在成年 PAH 中重新表达。通过 RNA 干扰或小分子化合物沉默,,, 或 E1A 相关蛋白 P300 () 可使 PAH 表型和动脉 FB 和平滑肌细胞中的间充质特征消退。P300/CREB 结合蛋白复合物的药理学抑制减少了远端肺血管的重塑，改善了血液动力学，并在体内三种啮齿动物模型中逆转了已建立的 PAH，以及减少了体外从人 PAH 肺组织中切取的组织切片中的血管重塑。与肺发育相关的 TF 的表观遗传再激活因此是 PAH 发病机制的基础，为治疗提供了机会。
