Jie Zheng, Yanan Zhang, Boyang Lv, Yuanyuan Ma, Xuecong Zhong, Junbao Du, Hongfang Jin, Yaqian Huang
Peking University First Hospital and Peking University.
China
Biomedicines
Biomedicines 2026;
DOI: 10.3390/biomedicines14040760
Abstract
Objectives: Downregulation of the endogenous gasotransmitter hydrogen sulfide (H2S) contributes to the pathogenesis of pulmonary arterial hypertension (PAH). While prophylactic H2S supplementation prevents PAH initiation in different rat models, its ability to reverse fully established PAH and pulmonary vascular structural remodeling is unknown. In this study, we aimed to test whether H2S donor therapy can reverse the existing PAH in a chronic-hypoxia rat model.
Methods: After 3 weeks of hypoxia exposure, rats with established hypoxia-induced pulmonary hypertension (HPH) were randomized to receive either continued hypoxia alone or hypoxia plus the H2S donor NaHS (56 μmol/kg·d, ip) for an additional 6 weeks. Pulmonary artery pressure, pulmonary artery muscularization, and right ventricular hypertrophy were assessed. Furthermore, the cell proliferation (Ki-67 and PCNA), ERK1/2 phosphorylation, and persulfidation of the endothelin type A receptor (ETAR) were examined and detected in rat lung tissues and pulmonary artery smooth muscle cells (PASMCs).
Results: H2S therapy effectively reversed established HPH and pulmonary artery structural remodeling, reducing RVSP, mPAP, and the proportion of fully muscularized small pulmonary arteries by 13.8%, 12.0%, and 62.7%, respectively. Moreover, the PAT/PET ratio was normalized to normoxic levels. The right ventricular hypertrophy index decreased by 29.2%. Mechanistically, H2S therapy suppressed PASMC proliferation, reduced ERK1/2 phosphorylation, and enhanced ETAR persulfidation. Furthermore, dithiothreitol-mediated reduction of ETAR persulfidation abrogated these antiproliferative effects of H2S therapy, establishing persulfidation as an obligatory mechanism.
Conclusions: H2S donor therapy effectively reverses established HPH and pulmonary vascular structural remodeling by inhibiting PASMC proliferation, which is linked to enhanced ETAR persulfidation. These data provide preclinical proof-of-concept for H2S-based interventions in patients with manifest PAH.
Category
Class III. Pulmonary Hypertension Associated with Alveolar Hypoxia
Animal Models of Pulmonary Vascular Disease and Therapy
Diagnostic Testing for Pulmonary Vascular Disease. Non-invasive Testing
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