Chien-Nien Chen, Nabil Hajji, Fu-Chiang Yeh, Sunniyat Rahman, Souad Ali, John Wharton, Nicoleta Baxan, Lin Zhao, Chong-Yang Xie, Yi-Guan Chen, Maria G. Frid, Prakash Chelladurai, Soni Savai Pullamsetti, Kurt R. Stenmark, Martin R. Wilkins, Lan Zhao
Imperial College London. Tri-Service General Hospital. University of Colorado. University Giessen Lung Centre. Max Planck Institute for Heart and Lung Research.
United Kingdom, Taiwan, United States and Germany
American Journal of Respiratory and Critical Care Medicine
Am J Respir Crit Care Med 2023;
DOI: 10.1164/rccm.202301-0181OC
Abstract
Rationale: Immune dysregulation is a common feature of pulmonary arterial hypertension (PAH). Histone deacetylase (HDAC)-dependent transcriptional reprogramming epigenetically modulates immune homeostasis and is a novel disease-oriented approach in modern times.
Objectives: To identify a novel functional link between HDAC and regulatory T cells (Tregs) in PAH, aiming to establish disease-modified biomarkers and therapeutic targets.
Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from idiopathic PAH (IPAH) patients and rodent models of pulmonary hypertension (PH): monocrotaline (MCT), Sugen5416-hypoxia (SuHx) rats and Treg-depleted mice. HDAC inhibitor Vorinostat (SAHA) was used to examine the immune modulatory effects in vivo, ex vivo and in vitro.
Measurements and main results: Increased HDAC expression was associated with reduced Foxp3+ Tregs and increased programmed cell death-1 (PD-1) signalling in PBMCs from IPAH patients. SAHA differentially modified a cluster of epigenetic-sensitive genes and induced Foxp3+ Treg conversion in IPAH T cells. Rodent models recapitulated these epigenetic aberrations and T cell dysfunction. SAHA attenuated PH phenotypes and restored FOXP3 transcription and Tregs in PH rats; interestingly, the effects were more profound in female rats. Selective depletion of CD25+ Tregs in SuHx mice neutralized the effects of SAHA. Furthermore, SAHA inhibited endothelial cytokine/chemokine release upon stimulation and subsequent immune chemotaxis.
Conclusions: Our results indicated HDAC aberration was associated with Foxp3+ Treg deficiency and demonstrated an epigenetic-mediated mechanism underlying immune dysfunction in PAH. Restoration of Foxp3+ Tregs by HDACi is a promising approach to resolve PH pathology, highlighting the potential benefit of developing “epigenetic therapies” for PAH.
Category
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Filed (PHiled). Greater than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: No