The Effects of Spironolactone on Inflammation in a Rodent Model of Pulmonary Arterial Hypertension

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Pulmonary arterial hypertension (PAH) encompasses a group of rare but lethal diseases characterized by progressive narrowing and occlusion of the small pulmonary arteries, stress on the right-side of the heart and eventually death from right-heart failure. New treatments are urgently needed because current therapy does not reverse this progressive disease and 50% of patients die within 7 years of their diagnosis. Inflammation has recently been recognized as an important part of the abnormal pulmonary arteries in patients with PAH, and therefore it has been hypothesized that drugs that block inflammation may have benefits in patients with PAH. While mineralocorticoid receptor (MR) independent anti-inflammatory effects of spironolactone (SPL) have been recognized for decades, the mechanism was poorly understood and the effects of SPL on inflammation in PAH have not been previously studied. Our group has uncovered an MR-independent mechanism whereby SPL suppresses inflammation in pulmonary artery endothelial cells in vitro. We identified XPB degradation as a shared, MR-independent mechanism by which SPL inhibits both NF-kB and AP-1 inflammatory signaling. Unlike SPL, eplerenone (EPL) did not cause XPB degradation and failed to suppress inflammatory signaling in vitro (Elinoff JM et al. Cardiovasc Res. 2018). Treatment with mineralocorticoid receptor (MR) antagonists beginning at the outset of disease, or early thereafter, prevents pulmonary vascular remodeling in pre-clinical models of PAH. However, the efficacy of MR blockade in established disease, a more clinically relevant condition, remains unknown. Therefore, we investigated the effectiveness of two MR antagonists, EPL and SPL, after development of severe right ventricular (RV) dysfunction in the rat SU5416-hypoxia (SuHx) PAH model. This study is completed and a manuscript describing the effects of MR antagonists on ventricular interdependence in the rat SuHx model of PAH was published in FY22 and summarized below. Cardiac magnetic resonance imaging (MRI) in SuHx rats at the end of week 5, prior to study treatment, confirmed features of established disease including reduced RV ejection fraction, RV hypertrophy, pronounced septal flattening with impaired left ventricular filling and reduced cardiac index. Five weeks of treatment with either EPL or SPL improved left ventricular filling and prevented the further decline in cardiac index compared to placebo. Interventricular septal displacement was reduced by EPL while SPL effects were similar, but not significant. Although MR antagonists did not significantly reduce pulmonary artery pressure or vessel remodeling in SuHx rats with established disease, animals with higher drug levels had lower pulmonary pressures. Consistent with effects on cardiac function, EPL treatment tended to suppress MR and proinflammatory gene induction in the RV. The inability of SPL metabolites to induce XPB-degradation, the relatively lower serum drug concentrations detected in vivo and the potential recovery of XPB protein levels during the intervals between drug consumption by Su/Hx rats may explain preserved RV and lung XPB protein expression and the lack of anti-inflammatory effects through this mechanism in SPL-treated animals. In conclusion, MR antagonist treatment led to modest, but consistent beneficial effects on interventricular dependence after the onset of significant RV dysfunction in the SuHx PAH model. These results suggest that measures of RV structure and/or function may be useful endpoints in clinical trials of MR antagonists in PAH patients.