Yong‐Jian Zhu, Jie‐Jian Kou, Ya‐Cong Bo, Meng‐Jie Zhang, Xin Fan, Lu‐Ling Zhao, Yi Yan, Hong Da Zhang, Wen‐Hui Wu, Ping Yuan, Yan Liu, Jun‐Zhuo Shi, Xiao‐Bin Pang, Yang‐Yang He
First Affiliated Hospital of Zhengzhou University. Huaihe Hospital and Henan University. Zhengzhou University. Shanghai Children’s Medical Center and Shanghai Jiao Tong University School of Medicine. Fuwai Hospital and Peking Union Medical College. Shanghai Pulmonary Hospital and School of Medicine Tongji University.
China
Journal of the American Heart Association
J Am Heart Assoc 2026;
DOI: 10.1161/JAHA.125.045580
Abstract
Background: Pulmonary arterial hypertension (PAH) is a progressive disease driven by pulmonary vascular remodeling, largely due to the abnormal proliferation and phenotypic switching of pulmonary artery smooth muscle cells.
Methods: Levels of topoisomerase II α were evaluated in the lungs from patients with idiopathic PAH, 2 rodent PAH models (SU5416 combined with hypoxia and monocrotaline-induced), and in pulmonary artery smooth muscle cells stimulated with platelet-derived growth factor BB (PDGF-BB). The therapeutic potential of amonafide, a topoisomerase II inhibitor, was also evaluated in these models. Integrated transcriptomic and metabolomic analyses were used to identify amonafide-regulated pathways. The role of neurotensin receptor 1 (NTSR1) was further investigated through overexpression and knockdown experiments in pulmonary artery smooth muscle cells.
Results: Topoisomerase II α was significantly upregulated in the lungs of patients with idiopathic PAH, SU5416 combined with hypoxia-, and monocrotaline-induced rodent PAH models, and PDGF-BB-stimulated pulmonary artery smooth muscle cells. This upregulation was associated with increased DNA damage and apoptosis resistance. Amonafide treatment markedly improved hemodynamics, attenuated right ventricular hypertrophy, and suppressed pulmonary vascular remodeling in both animal models. In vitro, amonafide inhibited PDGF-BB-induced pulmonary artery smooth muscle cell proliferation, migration, apoptosis resistance, and DNA damage. Mechanistically, amonafide downregulated NTSR1 expression and inhibited the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway. Crucially, NTSR1 overexpression abolished the beneficial effects of amonafide, whereas NTSR1 knockdown enhanced them.
Conclusions: Our findings unveil the pivotal role of amonafide in PAH pathogenesis and suggest that targeting topoisomerase II α and NTSR1 may be a promising therapeutic approach for treating PAH.
Category
Class I. Drug-induced and Toxin-induced Pulmonary Hypertension
Class III. Pulmonary Hypertension Associated with Alveolar Hypoxia
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Pulmonary Vascular Pathology
Medical Therapy. Efficacy or Lack of Efficacy
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes