Single-Cell Study of Two Rat Models of Pulmonary Arterial Hypertension Reveals Connections to Human Pathobiology and Drug Repositioning.

Rationale: The cellular and molecular landscape and translational value of commonly used models of pulmonary arterial hypertension (PAH) are poorly understood. Single-cell transcriptomics can enhance molecular understanding of preclinical models and facilitate their rational use and interpretation.Objectives: To determine and prioritize dysregulated genes, pathways, and cell types in lungs of PAH rat models to assess relevance to human PAH and identify drug repositioning candidates.Methods: Single-cell RNA sequencing was performed on the lungs of monocrotaline (MCT), Sugen-hypoxia (SuHx), and control rats to identify altered genes and cell types, followed by validation using flow-sorted cells, RNA in situ hybridization, and immunofluorescence. Relevance to human PAH was assessed by histology of lungs from patients and via integration with human PAH genetic loci and known disease genes. Candidate drugs were predicted using Connectivity Map.Measurements and Main Results: Distinct changes in genes and pathways in numerous cell types were identified in SuHx and MCT lungs. Widespread upregulation of NF-κB signaling and downregulation of IFN signaling was observed across cell types. SuHx nonclassical monocytes and MCT conventional dendritic cells showed particularly strong NF-κB pathway activation. Genes altered in SuHx nonclassical monocytes were significantly enriched for PAH-associated genes and genetic variants, and candidate drugs predicted to reverse the changes were identified. An open-access online platform was developed to share single-cell data and drug candidates (http://mergeomics.research.idre.ucla.edu/PVDSingleCell/).Conclusions: Our study revealed the distinct and shared dysregulation of genes and pathways in two commonly used PAH models for the first time at single-cell resolution and demonstrated their relevance to human PAH and utility for drug repositioning.

Oxidative Stress and Its Implications in the Right Ventricular Remodeling Secondary to Pulmonary Hypertension.

Pulmonary hypertension (PH) is a pulmonary vascular disease characterized by increased pulmonary artery pressures. Long standing pulmonary arterial pressure overload leads to right ventricular (RV) hypertrophy, RV failure, and death. RV failure is a major determinant of survival in PH. Oxidative stress has been associated with the development of RV failure secondary to PH. Here we summarize the structural and functional changes in the RV in response to sustained pulmonary arterial pressure overload. Furthermore, we review the pre-clinical and clinical studies highlighting the association of oxidative stress with pulmonary vasculature and RV remodeling in chronic PH. Targeting oxidative stress promises to be an effective therapeutic strategy for the treatment of RV failure.