Essential role of protein kinase R in the pathogenesis of pulmonary veno-occlusive disease
Year: 2025
Type: article
Abstract: Pulmonary veno-occlusive disease (PVOD) is a rare and severe subtype of pulmonary arterial hypertension, characterized by progressive remodeling of small pulmonary arteries and veins with no therapies. Using a mitomycin C-induced (MMC-induced) rat model, we previously demonstrated that protein kinase R-mediated (PKR-mediated) integrated stress response (ISR) drives endothelial dysfunction and vascular remodeling. To determine whether PKR is the primary mediator of ISR and the pathogenesis, we treated control (Ctrl) and PKR-knockout (KO) mice with the same dose of MMC. Consistent with rat data, Ctrl mice displayed ISR activation, vascular remodeling, and pulmonary hypertension after MMC treatment, while KO mice showed none of these phenotypes. Proteomic analysis revealed that MMC-mediated ISR activation attenuated protein synthesis in Ctrl but not in KO mice. These findings underscore the critical role of PKR-dependent ISR activation and subsequent perturbation of proteostasis as central mechanisms driving PVOD pathogenesis and identify PKR as a promising therapeutic target.
Source: JCI Insight
Authors: Amit Prabhakar, Rahul Kumar, Meetu Wadhwa, Abhilash Barpanda, Joseph Lyons, Asavari Gowda, Simren Gupta, Ananyaa Arvind, Prajakta Ghatpande, Arun P. Wiita, Brian B. Graham, Giorgio Lagna, Akiko Hata
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,100
Awards: G3334182221, Complement Mediated Remodeling in Pulmonary Vascular Disease, Hif2-alpha stabilization in Interstitial Macrophages Causes Thrombospondin-1 Mediated Hypoxic Pulmonary Hypertension, Molecular pathogenesis of pulmonary arterial hypertension, Elucidating the structural insights into the BMP receptor mutations in PAH, Activation, Phenotype and Function of CD4 T Cells in Schistosoma-Pulmonary Hypertension, Structural surfaceomics to probe conformation-selective immunotherapy targets
OpenAlex ID: W4413377786