Depletion of Protein Phosphatase 1 Results in Persistent Activation of the Integrated Stress Response and Age-Associated Exacerbation of Pulmonary Veno-Occlusive Disease

Pulmonary veno-occlusive disease (PVOD) is a form of pulmonary hypertension that affects individuals across the age spectrum. PVOD is characterized by the obstruction of small pulmonary vessels, causing increased pulmonary artery (PA) pressure and leading to right ventricular heart (RV) failure. Previous research showed that the administration of Mitomycin-C (MMC) in rats mediates PVOD through the activation of the eukaryotic initiation factor 2 (eIF2) kinase PKR and the integrated stress response (ISR), resulting in the impairment of vascular endothelial junctional structure and barrier function. In this study, we reveal that older rats experience more severe pulmonary vascular remodeling and RV hypertrophy than younger rats after MMC treatment due to lower levels of protein phosphatase 1, leading to prolonged eIF2 phosphorylation and ISR activation. We demonstrate that pharmacological blocking of the PKR-ISR pathway mitigates PVOD symptoms in both age groups, suggesting targeting the PKR-ISR axis as a potential PVOD therapeutic strategy.