Abstract 12699: Ferroptosis Inhibition Combats Pulmonary Vascular Remodeling and Improves RV-PA Coupling in Monocrotaline Rats

Introduction: Ferroptosis is an iron-dependent, non-apoptotic, highly inflammatory form of cell death. Ferroptosis is initiated by lipid peroxidation, and therefore ferroptotic cell death is sensitive to metabolic derangements, altered iron homeostasis, and oxidative stress. In the systemic circulation, ferroptosis inhibition improves endothelial cell function, but the role of ferroptosis in pulmonary arterial hypertension, a disease characterized by pulmonary arterial endothelial cell metabolic derangements and abnormal redox balance, is not well understood. Methods: Male Sprague Dawley rats were randomized into 3 groups: control, monocrotaline-vehicle (MCT-V), and MCT rats treated with a small molecule ferroptosis inhibitor (MCT-FI). Treatment started 14 days after MCT to improve translational potential. Pulmonary vascular disease severity, cardiomyocyte hypertrophy, and right ventricular (RV) function were assessed with histology, echocardiography, and closed-chest pressure-volume loop analysis. Results: Ferroptosis inhibition blunted pulmonary vascular disease severity as right ventricular systolic pressure and effective arterial elastance were significantly reduced and pulmonary arterial acceleration time was increased. Histological analysis demonstrated RV cardiomyocyte cross sectional area was lowered by ferroptosis antagonism. When evaluating RV function, echocardiography revealed an improvement in both tricuspid annular plane systolic excursion and RV free wall thickening while pressure-volume loop analysis showed RV-pulmonary artery (PA) coupling was restored by ferroptosis inhibition. Conclusions: Small molecule-mediated disruption of ferroptosis combated pulmonary hypertension and restored RV-PA coupling in MCT rats.