Ferroptosis Promotes Pulmonary Arterial Hypertension via Complement and Cytokine-Cytokine Interactions
Pulmonary arterial hypertension (PAH) is a deadly condition caused by the narrowing of the pulmonary arteries, which can lead to failure in the right ventricle (RV) of the heart. It has no known cure, but progress has been made in treating this disease (1). One such possibility for treatment lies within an iron-dependent form of cell death called ferroptosis (2). It was hypothesized that the inhibition of the cell signaling pathway involved in ferroptosis would reduce measures of pulmonary vascular disease burden in rodent models of PAH. Transcriptomics was also utilized to investigate through which pathways ferroptosis promotes PAH. In this study, male Sprague-Dawley rats were placed in three groups: control, monocrotaline-vehicle (MCT-V), and MCT rats treated with a small molecule ferroptosis inhibitor (MCT-FI). Following treatment, pulmonary vascular disease severity, cardiomyocyte hypertrophy, and RV function were assessed with histology, echocardiography, and closed-chest pressure-volume loop analysis. Additionally, RNA was extracted from lung tissue and sequenced. MetaboAnalyst was used with the transcriptomics data to generate correlational heatmaps, and it was determined which genes were significantly correlated with end-arterial elastance (Ea) and right ventricular systolic pressure (RVSP). These genes were processed using the Kyoto Encyclopedia of Genes and Genomes (KEGG), and ShinyGO was utilized to generate lollipop graphs containing pathways correlated with Ea and RVSP. The ferroptosis inhibitor reduced RVSP and Ea, improved RV-pulmonary artery coupling, and suppressed small pulmonary arterial vessel remodeling in MCT rats. The transcriptomics data showed RVSP was correlated with complement and the coagulation cascade, as well as cytokine-cytokine interactions. Ea was correlated with ferroptosis, complement, the coagulation cascade, and cytokine-cytokine interactions. This reveals the ferroptosis inhibitor likely acts on members of the complement, coagulation cascade, and cytokine-cytokine pathways to reduce the effects of ferroptosis and lessen the pulmonary vascular disease burden of PAH. References 1. Farber HW, Loscalzo J. Pulmonary Arterial Hypertension. N Engl J Med 2004; 351:1655–1665. 2. Li et al. Ferroptosis: past, present and future. Cell Death and Disease 2020; 11:88.