Abstract 2223 Multi-Omics Approaches to Discover Novel Mechanisms in Pulmonary Hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a chronic lung disease characterized by progressive increase in pulmonary arterial pressure leading to right ventricular (RV) failure and death. The molecular mechanisms causal in the development of PAH are not well understood. Recently, we demonstrated that oral administration of an oxidized lipid, 15-HETE (elevated in human PAH), is sufficient to cause PH in wild type C57BL/6 mice. Using this new model of PH, we conducted multi-omics analyses to identify novel pathways and mechanisms that participate in the development of PH. Methods/Results: 16S rRNA sequencing of the feces revealed that dietary 15-HETE causes dysbiosis, including a significant reduction in the abundance of short chain fatty acid (SCFA) producing bacteria. Supplementing drinking water of 15-HETE fed mice with 0.1M sodium butyrate (SB) attenuated the development of PH. Plasma metabolomics identified a decrease in cholesterol sulfate (CS) of PH mice that was reversed by SB. Using STITCH, we identified two genes connected to CS namely, RAR-related orphan receptor A (RORA) and RORC. RORA is a direct effector of nuclear receptor corepressor 1 (NCOR1), which we identified in RNA-seq data sets from both the jejunum and enterocytes of PH mice. We confirmed our findings by qPCR and demonstrated that NCOR1 expression in the jejunum of mice fed 15-HETE is decreased while SB supplementation prevented the decrease, mirroring the levels of CS. Conclusion: Using multiomics data from microbiome, metabolome, and transcriptome, we identified a novel pathway; butyrate-RORA-NCOR1-cholesterol sulfate, that participates in the development of PH in mice. This research is supported by T32HL144449, UCLA and Caltech integrated Cardiovascular Medicine for Bioengineers (iCMB) and by the National Heart, Lung, and Blood Institute grant 1R01HL162124-02.