The Sigma-1 receptor agonist PRE084 improves cardiopulmonary function and remodelling in an experimental model of pulmonary arterial hypertension

Sigma-1 receptors (S1R) are potential pharmacological targets for neurodegenerative diseases and cardiac pathologies, such as cardiac hypertrophy. S1R modulate several cellular functions by interacting with various proteins, including ion channels. Pulmonary arterial hypertension (PAH) is a severe disease characterised by exacerbated pulmonary vasoconstriction and pathological remodelling of the pulmonary vasculature, leading to right ventricular (RV) hypertrophy and eventual heart failure. Herein, we evaluated the therapeutic potential of the S1R agonist PRE084 in the hypoxia plus SU5416 (Hpx/Su) rat model of severe PAH. We found that treatment with PRE084 significantly improved the attenuated activity of K_V1.5 channels, reduced hypertrophy, and restored the resting membrane potential to physiological levels in pulmonary artery smooth muscle cells from Hpx/Su animals. This is associated with attenuated pulmonary vasoconstriction. Treatment with PRE084 also improved endothelium-dependent relaxation and attenuated pulmonary vascular remodelling in Hpx/Su rats. Notably, PRE084 ameliorated RV systolic pressure, RV dysfunction, hypertrophy, and fibrosis in Hpx/Su rats, as assessed through haemodynamic, echocardiographic, and histological evaluations. These effects were associated with the normalization of p-Akt expression and inositol levels in the RV. In summary, PRE084 markedly improved both the functional and morphological parameters characteristic of PAH, thereby attenuating disease progression. Collectively, our study suggests that targeting S1R may represent a promising therapeutic approach for the treatment of PAH.