Abstract 15964: Ferroptosis Integrates Mitochondrial Dysfunction and Pathological Inflammation to Promote Pulmonary Hypertension

Abstract

Introduction: Ferroptosis is an iron-dependent, mitochondrial-mediated, non-apoptotic, highly inflammatory form of cell death. Ferroptosis plays important roles in numerous disease states via activation of complement and NLRP3 inflammasome, but its role in pulmonary hypertension (PH) is less well defined. Methods: Male Sprague Dawley rats were randomized into 3 groups: control, monocrotaline-vehicle (MCT-V), and MCT rats treated with ferrostatin-1 (MCT-FI). Pulmonary vascular disease severity and right ventricular function were assessed with histology, echocardiography, and pressure-volume loop analysis. Mitochondrial enrichments from lung tissue were subjected to quantitative proteomics. RNAseq evaluated global lung expression changes. KEGG analysis was performed on proteomics and RNAseq datasets to delineate which pathways were most associated with PH severity and modulated by ferrostatin-1 treatment. The hemodynamic effects of single-nucleotide polymorphisms in GPX4 were evaluated in the BioVU dataset. Results: Ferroptosis inhibition reduced right ventricular systolic pressure and improved RV function in MCT rats. Proteomics analysis identified a link between ferroptosis and multiple metabolic pathways that were associated with PH severity. RNAseq demonstrated ferroptosis inhibition partially suppressed complement and inflammatory signaling. Finally, patients with SNP rs1444732 in GPX4 had a higher pulmonary vascular resistance and mean pulmonary arterial pressure. Conclusions: Ferroptosis may integrate disrupted metabolism and inflammation to promote pulmonary vascular disease.