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- Title
Restoration of Foxp3<sup>+</sup> Regulatory T Cells by HDAC-Dependent Epigenetic Modulation Plays a Pivotal Role in Resolving Pulmonary Arterial Hypertension Pathology.
- Authors
Chien-Nien Chen; Hajji, Nabil; Fu-Chiang Yeh; Rahman, Sunniyat; Ali, Souad; Wharton, John; Baxan, Nicoleta; Lin Zhao; Chong-Yang Xie; Yi-Guan Chen; Frid, Maria G.; Chelladurai, Prakash; Pullamsetti, Soni Savai; Stenmark, Kurt R.; Wilkins, Martin R.; Lan Zhao
- 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 were isolated from patients with idiopathic PAH (IPAH) and rodent models of pulmonary hypertension (PH): monocrotaline rats, Sugen5416-hypoxia rats, and Treg-depleted mice. HDAC inhibitor vorinostat (suberoylanilide hydroxamic acid, 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 Foxp31 Tregs and increased PD-1 (programmed cell death-1) signaling in peripheral blood mononuclear cells from patients with IPAH. SAHA differentially modified a cluster of epigenetic-sensitive genes and induced Foxp31 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 CD251 Tregs in Sugen5416-hypoxia 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 Foxp31 Treg deficiency and demonstrated an epigenetic-mediated mechanism underlying immune dysfunction in PAH. Restoration of Foxp31 Tregs by HDAC inhibitors is a promising approach to resolve pulmonary vascular pathology, highlighting the potential benefit of developing epigenetic therapies for PAH.
- Subjects
REGULATORY T cells; PULMONARY arterial hypertension; MONONUCLEAR leukocytes; HYDROXAMIC acids; EPIGENETICS; T cells
- Publication
American Journal of Respiratory & Critical Care Medicine, 2023, Vol 208, Issue 8, p879
- ISSN
1073-449X
- Publication type
Article
- DOI
10.1164/rccm.202301-0181OC